Superacid-promoted dual C-C bond formation by Friedel-Crafts alkylation and acylation of ethyl cinnamates: Synthesis of indanones

Article abstract of DOI:10.1055/s-0032-1318405

A superacid (triflic acid) promoted dual C-C bond formation via intermolecular Friedel-Crafts alkylation (Michael addition type) and intramolecular acylation for the efficient synthesis of 3-substituted indan-1-ones is presented. This method was successful in activating ethyl cinnamates towards dual aromatic electrophilic substitution. Moreover, it enabled us to synthesize novel spirotetracyclic systems. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318405

868▌
LETTER
lSetuterperacid-Promoted Dual C–C Bond Formation by Friedel–Crafts Alkylation
and Acylation of Ethyl Cinnamates: Synthesis of Indanones
Synthesis of Indanones
Bokka Venkat Ramulu, Alavala Gopi Krishna Reddy, Gedu Satyanarayana*
Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram 502 205, Medak District, Andhra Pradesh,
India
Fax +91(40)23016032; E-mail: gvsatya@iith.ac.in
Received: 01.02.2013; Accepted after revision: 17.02.2013
Dedicated to the memory of my mentor Prof. A. Srikrishna (1955–2013), an outstanding organic chemist and a constant source of inspira-
tion.
product was formed, rather gave the Friedel–Crafts ethyl-
Abstract: A superacid (triflic acid) promoted dual C–C bond for-
ated product (i.e., via the formation of ethyl carbocation
mation via intermolecular Friedel–Crafts alkylation (Michael addi-
electrophile).8 This anomaly is in good agreement and
reminiscent to that of observed deviations from linearity
tion type) and intramolecular acylation for the efficient synthesis of
3-substituted indan-1-ones is presented. This method was success-
ful in activating ethyl cinnamates towards dual aromatic electro- of the Hammet plot, for the hydrolysis of ethyl benzoates
philic substitution. Moreover, it enabled us to synthesize novel
spirotetracyclic systems.
bearing π-electron-withdrawing groups (i.e., an ideal ex-
ample for concave upward deviation, where it involves
Key words: cinnamates, indanones, Friedel–Crafts alkylation,
acylation, superacid
the AAL1 mechanism for the formation of ethyl carboca-
tion).9 Recently, the research group of Hashmi et al. re-
ported the use of gold Lewis acid catalysts in the Friedel–
Crafts reaction.10 There was a report by Klumpp et al. in
One-pot synthetic methods are considered to be the most 2004, using cinnamic acids as the source of dicationic in-
useful procedures in organic synthesis since they allow termediates, for the construction of 3-substituted indan-1-
constructing more than one bond in a single operation ones.5o Very recently, the same research group reported
without the need to isolate intermediates. Therefore, the another clever synthesis of indanones using more reactive
development of such one-pot processes which involves amides as acylating agents (i.e., by keeping the amide ni-
formation of multiple C–C bonds, particularly to construct trogen in extended conjugation with the π-electron-with-
cyclic structures, are of great interest because many cyclic drawing groups and thus acts as a good leaving group).5t
structures are identified as core structures of many biolog- Significance of the present method is based on the direct
ically active natural products. In this context, the Friedel– use of cinnamate esters unlike Klumpp’s approach,5o
Crafts reaction is considered as one of the most classical which was employed on cinnamic acids in the presence of
and powerful methods for forming C–C bond through al- a large excess of strong acid (100 equiv).
kylation and acylation reactions invented by Friedel and
The indanone moiety constitutes the core structural unit of
Crafts in 1877.1 Notably, in the last few decades this reac-
a variety of drugs and natural products which exhibit good
tion has been enormously exploited using various acids
range of biological activities. Representative examples of
(Brønsted and Lewis).2–4 Significantly, the synthesis of
such compounds are pauciflorol F,11 donepezil,12 indacri-
cyclic systems via single or multiple C–C bond formation
none,13 and taiwan-iaquinol B14 (Figure 1).
illustrates the power of the Friedel–Crafts reaction.5 The
importance of superelectrophiles came into light by
O
OH
OH
O
Olah’s research work in the seventies6 and later research-
ers made use of superelectrophiles and dicationic electro-
philes to construct ring systems efficiently,3b because they
are more reactive. Herein we disclose a simple and a prac-
tical method for the synthesis of 3-substituted indan-1-
ones based on a hitherto unexplored superacid (triflic ac-
id) mediated dual C–C bond formation via Friedel–Crafts
alkylation (Michael addition type) and acylation. There
were very few reports where esters were used as acylating
agents.7 Olah et al. reported the use of methyl benzoate as
the acylating agent and quite interestingly, when ethyl ac-
etate was used in place of methyl benzoate no acylated
HO
MeO
MeO
OH
N
OH
Bn
HO
plauciflorol F
donepezil
OH
O
Cl
O
i-Pr
H Me
Me
Cl
Ph
Me
MeO
HO2C
O
Me
OH
SYNLETT 2013, 24, 0868–0872
Advanced online publication: 06.03.2013
indacrinone
taiwaniaquinol B
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318405; Art ID: ST-2013-D0109-L
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Biologically active indanones

LETTER
Synthesis of Indanones
869
The required cinnamates for this study were prepared 1, entries 4 and 5). This gave a clear indication that the
from readily available benzaldehydes or corresponding enoate double bond is more reactive than the carbonyl
acetophenones using Wittig–Horner–Wadsworth–Em- bond of the ester function and thus preferentially alkylated
mons reaction. To sort out the best optimized reaction first. Subsequent increase of temperature as well as the
conditions based on the strength of the acid, the cinnamate quantity of the Lewis acid started to furnish the cyclized
1c (E-isomer) was treated with the external arene 2c under product 3c with the optimized yield 62% (Table 1, entries
different acidic conditions (Table 1). The initial attempts 6–10). The reaction in the presence of Brønsted superacid
either with PTSA or with TiCl4 were unsuccessful to yield (TfOH, 3 equiv) gave a promising result of 3c as an exclu-
any product (Table 1, entries 1–3). Whereas, the reaction sive product in very good yield (84%, Table 1 entry 11).
in the presence of Lewis acid (FeCl3) at ambient tempera- On the other hand, the reaction in the presence of gold cat-
ture gave only the alkylated product 4c, whose yield in- alysts proved to be unproductive (Table 1, entries 12 and
creased in parallel to the quantity of the acid used (Table 13).
Table 1 Optimization Conditions for the Synthesis of 3-Indanones 3c
OMe
O
O
CO2Et
Me
OEt
OMe
Me
Me
2c
acid
+
OMe
solvent
heat
OMe
OMe
OMe
1c
4c
3c
Entrya
Acid (equiv)
Solvent (mL)
Temp (°C)
Time (h)
Yield of 4c Yield of 3c
(%)b
(%)b
1
PTSA (0.2)
PTSA (0.3)
TiCl4 (0.3)
FeCl3 (0.3)
FeCl3 (0.7)
FeCl3 (0.7)
FeCl3 (3)
toluene (3)
DMF (2)
CH2Cl2 (2)
CH2Cl2 (2)
CH2Cl2 (2)
DCE (2)
120
140
r.t.
r.t.
r.t.
80
24
24
96
12
12
12
12
12
12
12
12
12
20
0c
0c
0c
30
69
18
12
0
0c
0c
0c
0e
0e
43
54
42
44
62
84
0
2
3
4
5
6
7
CHCl3 (2)
DCE (2)
60
8
FeCl3 (1.5)
FeCl3 (2)
80
9
DCE (2)
80
0d
0d
0d
0
10
11
12
13
FeCl3 (3)
DCE (2)
80
TfOH (3)
DCE (2)
80
(PPh3)3AuCl (0.05)
30% AuCl3 in dil. HCl (0.1)
DCE (2)
80
DCE (2)
100
9
0
a All reactions were carried out on 100 mg (1 equiv) scale of 1c (E-isomer) and 109 mg (1.5 equiv) of 2c.
b Isolated yields of chromatographically pure products.
c Neither 4c nor 3c were observed, only starting material was recovered.
d No 4c was formed.
e No 3c was identified.
Among the screened conditions, three equivalents of tri- and furnished the cyclized products 3a–k15 in very good
flic acid (Table 1, entry 11) turned out to be the best with to excellent yields (Scheme 1). It is noteworthy to mention
regard to the yield of indanone product 3c. Therefore, that this had been planned in such a way that the aromatic
these optimized conditions were applied to the other sys- moiety of all cinnamates 1a–f is more electron deficient
tems 1a–f (E-isomers) to examine the scope and limita- than that of the external arenes 2a–c employed. Therefore,
tions. Interestingly, these optimized reaction conditions only the external arene 2 was involved in the formation of
proved to be amenable for various systems possessing both new C–C bonds with the ethyl cinnamate 1.
electron-withdrawing and electron-donating substituents
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 868–872

870
B. Venkat Ramulu et al.
LETTER
O
CO2Et
R2
R3
R4
R2
+
TfOH (3 equiv)
R3
DCE, 80 °C
12–24 h
R1
R1
R4
1a–f
2a–c
3a–k
R1 = H, Cl
R2 = H, Me, Et
R3, R4 = H, Me, OMe
O
O
O
O
OMe
OMe
Cl
Cl
OMe
OMe
3a (91%)
3b (70%)
3c (90%)
3d (71%)
O
O
O
O
Me
Me
Me
Me
Me
OMe
Cl
Cl
OMe
3e (73%)
3f (75%)
3g (83%)
3h (84%)
O
O
O
Me
Me
Me
OMe
OMe
OMe
Cl
Cl
OMe
OMe
OMe
3i (88%)
3j (72%)
3k (72%)
Scheme 1 Superacid-promoted synthesis of indanones 3a–k from cinnamates 1a–f (E-isomers)
In order to check the feasibility of the reaction, we have Similar result was obtained, when the reaction was con-
explored the reaction on the Z-isomer 1cc. Gratifyingly, ducted on the mixture of E- and Z-isomers 1c and 1cc (4:1
the expected indanones 3e and 3h resulted in yields com- ratio) with the external arene 2c (Scheme 3).
parable to that of the E-isomers (Scheme 2).
Interestingly, when ethyl cinnamates 1a and 1c (E-iso-
mers) were treated with arene 2d, in the presence of triflic
acid, the simple benzene ring of ethyl cinnamate has been
O
EtO2C
involved in the intramoleclar Friedel–Crafts acylation af-
ter the initial Friedel–Crafts alkylation by 3-bromoanisole
(2d, Scheme 4). This may be due to the weakly deactivat-
ing inductive effect of 5-Br and 3-OMe groups to the in-
coming arylating moiety.
Me
R
TfOH (3 equiv)
Me
R
+
DCE, 80 °C
24 h
R
R
1cc
2a R = H
2c R = OMe
3e (79%)
3h (85%)
Scheme 2 Superacid-promoted synthesis of 3-indanones 3e and 3h
from the Z-isomer 1cc
O
CO2Et
Me
OMe
TfOH (3 equiv)
DCE, 80 °C
Me
+
OMe
OMe
24 h
OMe
3h (82%)
1c, 1cc
2c
Scheme 3
Synlett 2013, 24, 868–872
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Indanones
871
systems. Therefore, the enoate 1g treated with toluene
(2b) as well as veratrole (2c). Delightfully, the reaction
was successful at little lower temperature and furnished
the expected novel spirotetracyclic systems 3s and 3t
(Scheme 6). It has been observed that toluene (2b) plays a
dual role both as a solvent and external arene (Scheme 6).
CO2Et
Br
O
OMe
R1
R1
TfOH (3 equiv)
+
DCE, 80 °C
24 h
Br
OMe
3l (54%)
3m (92%)
1a R1 = H
1c R1 = Me
2d
CO2Et
Me
O
TfOH (3 equiv)
DCE, 50 °C
24 h, 61%
Scheme 4 Superacid-promoted synthesis of 3-indanones 3l and 3m
Me
+
(or)
Moreover, we also attempted the reaction where both the
aryl moieties can compete with each other in the intramo-
lecular acylation step after initial alkylation. Therefore,
two possible products were isolated, as expected, as an in-
separable mixture (Scheme 5).
TfOH (3 equiv)
toluene, 50 °C
24 h, 71%
1g
2b
3s
CO2Et
+
OMe
O
OMe
OMe
O
TfOH (3 equiv)
OMe
R2
DCE
50 °C, 24 h
67%
1g
2c
Me
Me
CO2Et
R2
3t
5n–p
2b
+
Scheme 6
TfOH (3 equiv)
O
DCE, 80 °C
12–24 h
R1
In summary, we have developed a simple and an efficient
one-pot dual C–C bond formation via an intermolecular
Friedel–Crafts alkylation (Michael addition type) and
subsequent intramolecular Friedel–Crafts acylation for
the synthesis of functionalized 3-substituted indan-1-
ones. This method was successfully applied to the synthe-
sis of novel spirotetracyclic systems. Further studies to
make use of this method for the preparation of various cy-
clic systems are in progress.
1a–c
R2
Me
R1
3n–p
O
O
Me
Me
3:1
3:1
3:1
3n (68%)
5n (23%)
Acknowledgment
Financial support by the Council of Scientific and Industrial Re-
search [(CSIR), 02(0018)/11/EMR-II], New Delhi, is gratefully
acknowledged. B.V.R and A.G.K. thank CSIR, New Delhi, for the
award of research fellowship.
O
O
Me
Cl
Cl
Me
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
3o (65%)
5o (21%)
r
t
iornat
O
O
References and Notes
Me
Me
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Me
Me
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3p (68%)
5p (22%)
Scheme 5 Superacid-promoted synthesis of indanones 3n–p and
5n–p from cinnamates 1a–c (E-isomers)
Furthermore, to check the scope and applicability of the
method, we explored the reaction on a cyclic equivalent of
cinnamate ester, for the synthesis of novel spirotetracyclic
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 868–872

872
B. Venkat Ramulu et al.
LETTER
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(15) General Procedure for Friedel–Crafts Alkylation and
Acylation of Ethyl Cinnamates (GP-1)
To an oven-dried Schlenk tube under nitrogen atmosphere
were added ester 1 (100 mg, 0.42–0.57 mmol), arene 2 (in
case of benzene, toluene, and xylene 12 equiv and for other
electron-rich arenes 1.5 equiv were used for 1 equiv of ester
1) and DCE (2 mL), followed by the addition of TfOH [3
equiv (i.e., 1.26–1.71 mmol)]. The resultant reaction mixture
was stirred at 80 °C for 12–24 h. Progress of the reaction
was monitored by TLC until the reaction was completed.
The reaction mixture was quenched by the addition of aq
NaHCO3 and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with sat. NaCl
solution, dried (Na2SO4), and concentrated under reduced
pressure. Purification of the residue by silica gel column
chromatography (PE–EtOAc) furnished the indanone 3 (54–
92%).
Representative Analytical Data
Compound 3f: IR (MIR-ATR, 4000–600 cm–1): 2966, 2930,
1710, 1602, 1491, 1462, 1288, 1234, 1151, 1093, 1012, 828,
762, 674, 582 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.78
(d, 1 H, J = 7.3 Hz, ArH), 7.60 (dd, 1 H, J = 7.8, 7.3 Hz,
ArH), 7.43 (dd, 1 H, J = 7.8, 7.3 Hz, ArH), 7.25 (d, 1 H, J =
7.8 Hz, ArH), 7.24 (ddd, 2 H, J=8.8, 2.4, 2.4 Hz, ArH), 7.10
(ddd, 2 H, J = 8.8, 2.4, 2.4 Hz, ArH), 2.91 (d, 1 H, J = 19.1
Hz, CHaHbCO), 2.88 (d, 1 H, J = 19.1 Hz, CHaHbCO), 1.81
[s, 3 H, ArC(CH2CO)CH3] ppm. 13C NMR (100 MHz,
CDCl3): δ = 205.3 (s, C=O), 162.3 (s, ArC), 145.8 (s, ArC),
135.6 (s, ArC), 135.4 (d, ArCH), 132.3 (s, ArC), 128.5 (d, 2
C, ArCH), 128.0 (d, ArCH), 127.7 (d, 2 C, ArCH), 125.4 (d,
ArCH), 123.4 (d, ArCH), 55.5 (t, CH2CO), 45.6 [s,
ArC(CH2CO)CH3], 28.3 [q, ArC(CH2CO)CH3] ppm. HRMS
(APCI+): m/z calcd for [C16H14ClO]+: 257.0728 [M + H]+;
found: 257.0724.
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Compound 3g: IR (MIR-ATR, 4000–600 cm–1): 2964, 2851,
1705, 1581, 1488, 1399, 1282, 1244, 1160, 1093, 826, 724,
665, 588 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.57 (s, 1
H, ArH), 7.42 (d, 1 H, J = 7.8 Hz, ArH), 7.22 (ddd, 2 H, J =
8.8, 2.4, 2.4 Hz, ArH), 7.14 (d, 1 H, J = 7.8 Hz, ArH), 7.10
(ddd, 2 H, J = 8.8, 2.4, 2.4 Hz, ArH), 2.89 (d, 1 H, J = 19.1
Hz, CHaHbCO), 2.87 (d, 1 H, J = 19.1 Hz, CHaHbCO), 2.42
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(b) Gerald Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L.
Adv. Synth. Catal. 2003, 345, 1247. (c) Hashmi, A. S. K.;
Schwarz, L.; Rubenbauer, P.; Blanco, M. C. Adv. Synth.
Catal. 2006, 348, 705.
(s, 3 H, ArCH3), 1.78 [s, 3 H, ArC(CH2CO)CH3] ppm. 13
NMR (100 MHz, CDCl3): δ = 205.4 (s, C=O), 159.7 (s,
C
ArC), 146.1 (s, ArC), 138.0 (s, ArC), 136.6 (d, ArCH), 135.9
(s, ArC), 132.2 (s, ArC), 128.5 (d, 2 C, ArCH), 127.6 (d, 2
C, ArCH), 125.1 (d, ArCH), 123.3 (d, ArCH), 55.8 (t,
CH2CO), 45.3 [s, ArC(CH2CO)CH3], 28.3 [q,
ArC(CH2CO)CH3], 21.1 (q, ArCH3) ppm. HRMS (APCI+):
m/z calcd for [C17H16ClO]+: 271.0884 [M + H]+; found:
271.0880.
Synlett 2013, 24, 868–872
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