Superacid mediated intramolecular condensation: Facile synthesis of indenones and indanones

Article abstract of DOI:10.1039/c5ra12234a

Superacid promoted intramolecular acylation is described for the synthesis of indenones. Interestingly, in all resulting indenones, the olefin bond is rearranged to the exo position of the five membered rings. Significantly, the method is further applied to the synthesis of indanones via the formation of two C-C bonds by in situ treatment of indenones with an external arene, in one-pot. Most importantly, the present sequential method for the synthesis of indanones is advantageous, as it limits even more electron rich external arenes only to the Friedel-Crafts alkylation. This is not possible in previous reports wherein both cinnamic acid ester and the external arenes are treated together in the presence of an acid, wherein the relatively more reactive arene is preferred to facilitate the acylation step.

Full text of DOI:10.1039/c5ra12234a

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Superacid mediated intramolecular condensation:
facile synthesis of indenones and indanones†
Cite this: RSC Adv., 2015, 5, 70972
*
Bokka Venkat Ramulu and Gedu Satyanarayana
Received 24th June 2015
Accepted 10th August 2015
DOI: 10.1039/c5ra12234a
www.rsc.org/advances
Superacid promoted intramolecular acylation is described for the prepared by employing the Friedel–Cras and metal-catalysed
synthesis of indenones. Interestingly, in all resulting indenones, the reactions.8 Some notable Pd-catalyzed annulations for the
olefin bond is rearranged to the exo position of the five membered synthesis of indenones have been noted from the research
rings. Significantly, the method is further applied to the synthesis of groups of Larock,9 Chiusoli,10 Buchwald11 and Li.12 Nagao13 et al.
indanones via the formation of two C–C bonds by in situ treatment of reported the formation of indenones from allenyl aryl ketones
indenones with an external arene, in one-pot. Most importantly, the upon treatment with BF3$OEt2. Liang and co-workers disclosed
present sequential method for the synthesis of indanones is advan- the synthesis of indenones under gold catalyzed tandem rear-
tageous, as it limits even more electron rich external arenes only to the rangement.14 While, the research group of Ohwada reported
Friedel–Crafts alkylation. This is not possible in previous reports triic acid promoted cyclization for the synthesis of indenes
wherein both cinnamic acid ester and the external arenes are treated and dihydro naphthalenes.15 Womack disclosed synthesis of
together in the presence of an acid, wherein the relatively more indanones and indenols from 2-alkylcinnamaldehydes via
reactive arene is preferred to facilitate the acylation step.
intramolecular Friedel–Cras reaction using FeCl3.16 On the
other hand, Klumpp17 and Fillion18 co-workers reported the
synthesis of indanones under Friedel–Cras acylation
conditions.
Normally, the classical intramolecular Friedel–Cras acyla-
tion works between an acyl halide or carboxylic acid or anhy-
dride with an aromatic ring under acid promoter (Lewis or
Brønsted). Lewis acid promoted intramolecular Friedel–Cras
acylation of acyl halides are not familiar. Whereas, intra-
molecular acylation protocols by direct use of carboxylic acids
Among the classical reactions for the creation of C–C bonds, the
Friedel–Cras reaction turned out to be one of the most
powerful techniques towards aromatic electrophilic substitu-
tions.1 In particular, for the past few decades there were
numerous applications of this reaction under different acidic
conditions (Brønsted/Lewis).2–4 Particularly, the intramolecular
acylation of this protocol was found to be ideal as it constructs
the carbocyclic systems; many natural products and drugs are
cyclic compounds. In this regard, indanones and indenones are
essential carbocyclic compounds as they constitute natural as
well as pharmaceutical products. Some of the biologically
important natural and unnatural indanones/indenones are
shown in Fig. 1.5 Their interesting biological activities promp-
ted organic chemists to develop new synthetic methods towards
their synthesis. In the past decades, many methods have been
developed for the synthesis of indanones/indenones. For
example, indanones were synthesized using the Friedel–Cras,
Rh-catalysis6 and Nazarov cyclizations.7 Also, indenones were
Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus,
Yeddumailaram – 502 205, Medak District, Telangana, India. E-mail: gvsatya@iith.
ac.in; Fax: +91 40 2301 6032
† Electronic supplementary information (ESI) available. CCDC 1408325. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c5ra12234a
Fig. 1 Naturally occurring and pharmaceutically important indanones/
indene/indenones.
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as carbocation equivalents suffer due to the poor leaving nature manner. In the earlier report for synthesis of indanones, rela-
of the hydroxyl group, hence require forceful conditions. For tively more electron rich aromatic ring was involved in acylation
Meldrum's acids, competition studies for the rate of intra- step. Whereas, the present sequential strategy, allows the acyl-
molecular acylation is determined to be tetralone > benzosu- ation exclusively by the ring that is derived from cinnamic acid
berone > indanone. Therefore, synthesis of ve-membered ester, thereby limiting the external arene only to alkylation step
ketones (1-indanones) might be feasible under harsh condi- irrespective of its reactive nature.
tions. In addition, direct synthesis of indanones starting from
To initiate the synthetic study, the required b-alkyl cinna-
esters using intramolecular Friedel–Cras acylations are not mates 1 were readily synthesized from the corresponding
familiar. However, use of Meldrum's acid for the synthesis of carbonyl compounds (benzaldehydes or corresponding
carbocyclic ketones under mild Friedel–Cras conditions is very ketones) under standard Wittig–Horner–Wadsworth–Emmons
good alternative. In 2008, the research group of Baba reported19 conditions. As a model study, the b-methyl cinnamic acid ester
acylation of arenes with esters by dimethylchlorosilane and 1a was explored under different set of acidic conditions to sort
indium tribromide. As part of our ongoing research interests in out optimized conditions and the results are as summarized in
domino or sequential domino one-pot process, very recently, we Table 1. Therefore, initially our previously established condi-
have developed a super acid promoted synthesis of indanones tions for the synthesis of indanones were applied on b-methyl
starting from simple cinnamic acid esters.20 In this study, the cinnamic acid ester 1a. However, no progress was seen and led
generality and scope of this method has been well studied by to recovery of the starting material 1a (Table 1, entry 1). Almost
synthesizing numerous compounds. We also developed a same trend has been noticed with CHCl3 and Lewis acids (FeCl3
practical method for the direct synthesis of highly substituted and BF3$OEt2) as well (Table 1, entries 2–4). Neither the product
indanones from very simple aryl isopropyl ketones and benz- 2a nor the starting material 1a was isolated when H2SO4 and
aldehydes promoted by super acid (Scheme 1).21 Though, the AlCl3 were used (Table 1, entries 5–6). Interestingly, the expec-
Friedel–Cras cycloacylation was known with acid chlorides ted product 2a was observed but with the double bond isom-
and carboxylic acids, the corresponding esters have not been erization to exo-cyclic position of the ve membered ketone by
used for this purpose. This may be due to their less reactivity. increasing the amount of TfOH (Table 1, entry 7). Interestingly,
With this back ground, we envisioned that the direct treatment further increase of TfOH (20 equiv.), gave the indenone 2a in
of simple cinnamic acid esters under strong acidic conditions, fair yield (Table 1, entry 8). Gratifyingly, the reaction with 24
would lead to the formation of indenones. Here in, we describe equiv. of TfOH, furnished the indenone 2a in very good yield
an efficient and practical method for the synthesis of indenones (87%, Table 1, entry 9). However, no progress was noticed with
using triic acid as the promoter under Friedel-Cras acylation more equivalents of mild Lewis acid BF3$OEt2 (Table 1, entry
conditions. To the best of our knowledge, there were no reports 10). Signicantly, the preference of rearranged olen bond to
on the direct intramolecular acylation of cinnamic acid esters.
Also, unlike our previous report(s), the present method was
applied for the synthesis of indanones in a sequential one-pot
Table 1 Optimizing conditions for the formation of indenone 2a
starting from 1a
Yieldb (%)
Entrya Acid (equiv.) Solvent (mL) Temp (ꢀC) Time (h) 2a
1
2
3
4
5
6
7
8
9
10
TfOH (3)
TfOH (3)
FeCl3 (3)
BF3$OEt2 (3) DCE (2)
H2SO4 (3)
AlCl3 (3)
TfOH (10)
TfOH (20)
TfOH (24)
DCE (2)
CHCl3 (2)
DCE (2)
80
80
80
80
80
80
RT
RT
RT
80
12
12
12
12
12
12
12
12
8
0c
0c
0c
0c
—
—
50%e
72%
87%
0c
d
d
DCE (2)
DCE (2)
DCE (2)
DCE (2)
DCE (2)
BF3$OEt2 (20) DCE (2)
12
a
All reactions were carried out on 95 mg (0.5 mmol) scale of 1a and
b
solvent DCE (2 mL). Yields of chromatographically pure products.
c
d
Only starting material 1a was recovered. Neither the product 2a
e
nor starting material 1a was recovered. Starting material 1a was also
recovered.
Scheme 1 Comparison of the present vs. previous approaches.
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the exo position to ring reveals its unusual stability over the
endo double bond isomer. This present study is further sup-
ported by the previous reports for the synthesis of indenones
under various conditions, wherein the olen bond is placed at
exo position of the ring as well.10–14
To check the scope and generality of the method, we have
applied the above established conditions (Table 1, entry 9) to
other b-alkyl cinnamic acid esters 1b–1t and the results are as
summarized in Table 2. Delightfully, the protocol was quite
successful and amenable for the systems with different
substituents and gave the corresponding indenones 2a–2t with
di-, tri- and tetra-substituted exo-cyclic olens, in very good to
excellent yields (Table 2). It is worth mentioning that in the case
of similar aromatic systems such as phenyl/naphthyl/alkyl
substituent on the ring (2a, 2f, 2g, 2o, 2p & 2q), the reaction
was quite successful under established conditions [i.e. TfOH
(24 equiv.), 8 to 12 h, RT]. On the other hand, usually, the
reaction with electron rich aromatic rings (2b–2e, 2h–2n & 2r–
2t) completed quickly even with low amount of triic acid
(3 equiv.). Notably, the substrate scope has been well studied
Scheme 2 Comparing the technical differences between the present
and previous results.
Table 2 Synthesis of indenones 2 via intramolecular acylation from cinnamic acid esters 1a,b
a
All reactions were carried out on 0.5 mmol scale of 1. b Yields of chromatographically pure products.
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Table 3 Synthesis of indanones 4 from cinnamic acid esters 1 via intramolecular acylation and intermolecular arylationa,b
a
b
All reactions were carried out on 0.5 mmol scale of 1. Yields of chromatographically pure products.
with simple to electron rich aromatic rings and with different b-
Gratifyingly, as expected, the sequential one-pot protocol
alkyl substituents (methyl, ethyl, n-propyl & iso-propyl) as well. was found successful and furnished the corresponding inda-
Unless otherwise noted, for each system, the reaction was nones 4a–4j (Table 3). Signicantly, unlike our previous method
explored at least two to four times, under varying amount of the for the synthesis of indanones (in which the relatively more
acid and time, and the best conditions are presented in Table 2. electron rich aromatic ring selectively participated in the Frie-
In addition to the NMR data for the stereochemistry of the exo- del–Cras acylation step), the present method limits the
cyclic olen is unambiguously conrmed from the single crystal external arene to only Friedel–Cras alkylation irrespective of
X-ray diffraction analysis of 2m (see, ESI†).
its electron poor/rich nature. However, the reaction was smooth
Furthermore, to extend the method, synthesis of substituted for simple acetophenone derived cinnamic acid esters, but in
indanones containing quaternary carbon atom was planned, in case of higher b-alkyl cinnamic acid esters, the reaction was not
a sequential one-pot manner. It was anticipated that treatment successful. This may be due to more thermodynamic stability of
of in situ generated indenone with an external arene would more substituted double bond of the intermediate indenone 2.
deliver indanones in a complimentary mode to our previous On the other hand, under forceful conditions led to the
method for the synthesis of indanones (Scheme 2).20
decomposition of the reaction mixture.
A plausible reaction mechanism for the formation of
indenones 2 and indanones 4 is shown in Scheme 3. Initially,
the protic acid could activate and isomerize the double bond of
the ester 1 to yield the equilibrating structures A and B Intra-
molecular acylation of B and rearomatization leads to the
indenone 2. Further, in situ treatment of indenone 2 with an
external arene 3 affords indanone 4.
Conclusions
We have disclosed an efficient method for the synthesis of
indenones via intramolecular Friedel–Cras acylation and
double bond isomerization of cinnamic acid esters. Further, the
protocol was extended to the synthesis of indanones by treat-
ment of in situ generated indenones with external arenes.
Notably, the present method limits the external arene only to
Scheme
indenones 2 and indanones 4.
3 Plausible reaction mechanism for the formation of
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the Friedel–Cras alkylation which was not possible in our
previous protocol for the synthesis of indanones.
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Acknowledgements
We are grateful to the Department of Science and Technology-
Science and Engineering Research Board (DST-SERB) [No.: SB/
S1/OC-39/2014], New Delhi, for the nancial support. B. V. R.
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