Non-conventional methodologies in the synthesis of 1-indanones

Article abstract of DOI:10.3390/molecules19055599

1-Indanones have been successfully prepared by means of three different non-conventional techniques, namely microwaves, high-intensity ultrasound and a Q-tube reactor. A library of differently substituted 1-indanones has been prepared via one-pot intramolecular Friedel-Crafts acylation and their efficiency and "greenness" have been compared.

Full text of DOI:10.3390/molecules19055599

Molecules 2014, 19, 5599-5610; doi:10.3390/molecules19055599
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Non-Conventional Methodologies in the Synthesis of 1-Indanones
Manuela Oliverio 1, Monica Nardi 2, Paola Costanzo 1, Luca Cariati 1, Giancarlo Cravotto 3,
Salvatore Vincenzo Giofrè 4 and Antonio Procopio 1,*
1
Dipartimento di Scienze della Salute, Università Magna Graecia, Viale Europa,
Germaneto (CZ) 88100, Italy; E-Mails: m.oliverio@unicz.it (M.O.); pcostanzo@unicz.it (P.C.);
lucacariati@hotmail.it (L.C.)
2
Dipartimento di Chimica, Università della Calabria, Cubo 12C, Arcavacata di Rende (CS) 87036,
Italy; E-Mail: monica.nardi@unical.it
3
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via Pietro Giuria 9,
Torino 10125, Italy; E-Mail: giancarlo.cravotto@unito.it
4
Dipartimento Scienza del Farmaco e Prodotti per la salute, Università di Messina,
Via Santissima Annunziata, Messina 98168, Italy, E-Mail: sgiofre@unime.it
* Author to whom correspondence should be addressed; E-Mail: procopio@unicz.it;
Tel.: +39-0961-369-4020; Fax: +39-0961-369-4237.
Received: 2 April 2014; in revised form: 19 April 2014 / Accepted: 23 April 2014 /
Published: 30 April 2014
Abstract: 1-Indanones have been successfully prepared by means of three different
non-conventional techniques, namely microwaves, high-intensity ultrasound and a
Q-tube™ reactor. A library of differently substituted 1-indanones has been prepared via
one-pot intramolecular Friedel-Crafts acylation and their efficiency and “greenness” have
been compared.
Keywords: 1-indanones; microwaves; ultrasound; Q-tube™; Friedel-Crafts acylation
1. Introduction
In the last two decades, environmental issues linked to the chemical and associated industries, such
as the pharmaceutical industry, have become increasingly pertinent. Many classical synthetic
methodologies require large amounts of natural resources and generate copious amounts of waste [1].

Molecules 2014, 19
5600
Thus, the need to incorporate green chemistry into the synthesis of active pharmaceutical ingredients
and intermediates is of primary importance for the pharmaceutical industry [2].
Indanones and related compounds are important bioactive molecules. These compounds have
exhibited biological activity against cancer cells and Alzheimer’s disease; moreover they can be used
as synthetic intermediates for several drugs and as precursors to natural products [3–10]. Other
applications include their use as ligands in olefinic polymerization catalysts [11–20] and as discotic
liquid crystals [21]. The most famous drug which bears an indanone moiety is probably donepezil
hydrochloride, which has been approved by the United States Food and Drug Administration (US-
FDA) for the treatment of mild-moderate Alzheimer’s disease [22]. The intramolecular Friedel-Crafts
cyclization reaction of 3-arylpropionic acids or chlorides is one of the most common methods for the
preparation of 1-indanones [23–29]. Although the direct dehydrative cyclization of 3-arylpropionic
acids is more difficult than cyclization via acid chlorides, it is preferable because of the environmental
benefits it provides. In fact, the “one-step reaction” produces water as the only by-product while the
“two-step reaction” generates a large amount of toxic and corrosive compounds. Nevertheless, direct
cyclization usually requires an excess of protic acids (even as solvents) such as sulfuric acid, hydrogen
fluoride [30], polyphosphoric acid [31], methanesulfonic acid (MSA) [32], a mixture of MSA and
P2O5 [33], or Lewis acids such as AlCl3 and SnCl4 [30]. Some lanthanide triflates, in particular
Tb(OTf)3, were reported to be useful catalysts for the dehydrative cyclization of 3-arylpropionic acids
to form 1-indanones [34] in o-chlorobenzene at very high temperatures. We report herein an improved
method for the synthesis of 1-indanone derivatives which proceeds via the superacid-catalyzed
intramolecular Friedel-Crafts acylation of 3-arylpropionic acids.
As mentioned above, the examples of direct intramolecular Friedel-Crafts acylation of 3-arylpropionic
acids to produce 1-indanone derivatives are very far from satisfying many green chemistry principles
since they are performed under extremely drastic experimental conditions, such as elevated reaction
temperatures (250 °C in chlorobenzene) and require very long reaction times [23–34]. In light of the
enormous diffusion and application of non-conventional techniques in the implementation of synthetic
green processes [35–38], and our own experience in this field [39–44], we decided to explore the use
of microwave irradiation (MW), high-intensity ultrasound (US) and high-pressure conditions to
develop a greener synthesis of 1-indanone derivatives via the intramolecular Friedel-Crafts acylation of 3-
arylpropionic acids.
2. Results and Discussion
To start our investigation, it was decided to study the cyclization of 3-(4-methoxyphenyl)propionic
acid (1) in different solvents and experimental conditions using Tb(OTf)3 as the Lewis acid, the best
reported in the literature [34], and triflic acid [27] (Scheme 1). All attempts to perform the
MW-assisted Tb(OTf)3 catalyzed reaction in environmentally benign solvents such as PEG, n-butanol,
ethyl lactate or water, or even in slightly activated aromatic solvents failed (Table 1, entries 1–6).
A negative result was also observed when the reaction was performed in inert high boiling solvents
such as isooctane (Table 1, entry 7) and only in chlorobenzene a good conversion of substrate was
observed after only 60 min, albeit affording a low yield of product 1a (Table 1, entry 8).

Molecules 2014, 19
Scheme 1. Synthesis of 1-indanone 1a via the cyclization of 3-(4-methoxyphenyl)
5601
propionic acid 1 under US or MW irradiation.
O
catal/solvent
MW or US
OH
H3CO
H3CO
1
1a
O
Table 1. MW vs. US in the intramolecular Friedel-Craft acylation of 3-(4-methoxyphenyl)
propionic acid (1).
Entry Catalyst (%mol)
Solvent
PEG a
T (°C)
180
180
180
180
180
180
250
250
25
Method
MW
MW
MW
MW
MW c
MW c
MW c
MW
r.t.
Time (min) Conv. (%) Yield (%)
1
2
Tb(OTf)3 (20)
Tb(OTf)3 (20)
Tb(OTf)3 (20)
Tb(OTf)3 (20)
Tb(OTf)3 (20)
Tb(OTf)3 (20)
Tb(OTf)3 (20)
Tb(OTf)3 (20)
TfOH (10 eq.)
TfOH (3 eq.)
TfOH (1 eq.)
TfOH (2 eq.)
TfOH (3 eq.)
TfOH (3 eq.)
TfOH (5 eq.)
TfOH (10 eq.)
TfOH-SiO2 (30)
TfOH-SiO2 (30)
30
30
-
-
-
-
n-BuOH a
3
Ethyl lactate a
H2O
Toluene b
Xylene b
30
-
-
4
30
-
-
5
30
10
-
10
-
6
30
7
Isooctane c
Cl-benzene
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
CH2Cl2 (dry)
10
-
-
8
60
85
85
100
50
75
100
-
33 d
61 d
100
20 d
53 d
100
-
9
1440
60
10
11
12
13
14
15
16
17
18
80
MW
MW
MW
MW
US
80
120
60
80
110
40
30
120
1260
150
60
40
US
80
100
-
80
100
-
40
US
110
40
MW
US
60
-
-
a
b
Formation of side-esterification or trans-esterification by-products; Formation of intermolecular Friedel-Craft
c
acylation by-products; Reaction conducted in the presence of a SiC tablet used as a MW inert absorbent;
d Formation of by-products.
Clearly improved results were obtained when the reaction was catalyzed by a large excess of triflic
acid (TfOH) in CH2Cl2. As previously reported in the literature [27], a 61% yield of 1a was observed
at room temperature, but only after a very long reaction time (Table 1, entry 9), whereas complete
conversion of substrate 1 to indanone 1a was observed after only 60 min when the reaction was
performed under MW at 80 °C using three equivalents of TfOH (Table 1, entry 10).
Lower amounts of catalyst gave poorer yields due to the considerable number of by-products
formed (Table 1, entries 11 and 12). The same positive result was registered in only 30 min when the
reaction temperature was raised to 110 °C (Table 1, entry 13). Comparable results were registered
when the same reaction was accomplished under US, however, the complete conversion of the
substrate 1 to indanone 1a was observed in an acceptable reaction time only when a large excess of
triflic acid was used in CH2Cl2 at 40 °C (Table 1, entries 14–16). Triflic acid is a highly corrosive and

Molecules 2014, 19
5602
fuming liquid. It is the strongest Brønsted acid, having a Ho value of 14.1. Unmodified
chromatographic silica gel-supported triflic acid has very recently been proposed as an efficient and
recyclable catalyst under solvent free conditions [45]. Thus, in an attempt to add this more
environmentally friendly way to use this superacid to our synthetic protocol, the test reaction reported
in Scheme 1 was also performed using silica gel supported triflic acid (TfOH-SiO2). Unfortunately, no
conversion (of substrate 1) was observed after 60 min under MW or US (Table 1, entries 17 and 18). In
a last test, the MW- and US-assisted reactions were performed in significantly lower reaction times in
dry CH2Cl2, to give quantitative yields of product 1a and avoiding the formation of by-products. All
the attempts to use more environmentally acceptable solvents gave scarce results, leaving dry CH2Cl2
as the best choice for performing the reaction reported in Scheme 1.
Performing the reaction in dry CH2Cl2 permitted the total conversion of the substrate 1 into 1a in 60 min
at 80 °C using only 3 equivalents of TfOH (Table 1 entry 10). On the other hand, in the US-assisted
protocol, the same reaction was performed at lower temperature with a cleaner reaction profile and
simplified work-up, despite the significantly higher amount of catalyst necessary to obtain the
quantitative conversion of 1 into 1a.
In the attempt to unify the advantages of both assisted methods, the reaction pictured in Scheme 1
was performed in the Q-tube™ which is a safe pressure reactor which features a patent pending
pressure-release and reseal system that prevents accidental explosions due to over–pressurization.
Q-tube™ is an affordable alternative to expensive and cumbersome MW synthesizers; this system
enables a reaction to be carried out at higher temperature than the boiling point of solvents and
reagents, which will increase the reaction rate.
The results reported in Table 2, clearly confirm the efficiency of Q-tube™ as a valid alternative
technique (Table 2, entry 1), which provides a cleaner reaction profile very similar to what is observed
in the US-assisted protocol. Longer reaction times did not improve the reaction performance and only
traces of product 1a were obtained at 150 °C (Table 2, entries 2 and 3). It is of interest to know if
Tb(OTf)3, the most active Lewis acid reported in literature for this process, can be used as catalyst in
the Q-tube experiments. A poor result was registered when the reaction was carried out in
chlorobenzene as reported [34] (Table 2, entry 4), whereas a good yield of product 1a was obtained
when the reaction was performed in toluene (Table 2, entry 5).
Very poor results were obtained when the reaction was performed in high-boiling point
hydrocarbon solvents and at very high reaction temperatures (Table 2, entries 7 and 8). Finally, the
endeavor to carry out the reaction again using silica gel-supported triflic acid in CH2Cl2 gave a
negative result (Table 2, entries 9 and 10) leaving the following three experimental procedures as the
best choices for the reaction depicted in Scheme 1; triflic acid is added at 0 °C to a solution of
0.5 mmol of substrate in dry CH2Cl2, then the solution is heated to room temperature and the reaction
is conducted under MW- or US-assistance or in the Q-tube™ (Table 1 entries 10, 16 and Table 2 entry
1 respectively). The best experimental conditions obtained with MW, US- and Q-tubeTM protocols
were applied to several substrates (Scheme 2) with the aim of testing the applicability of the methods
and comparing their efficiency and versatility (Table 3).

Molecules 2014, 19
Table 2. Q-Tube method in the intramolecular Friedel-Craft acylation of 3-(4-methoxyphenyl)
5603
propionic acid 1.
Entry Catalyst (%mol)
Solvent
CH2Cl2 (dry)
CH2Cl2(dry)
CH2Cl2(dry)
C6H5Cl
toluene
n-C7H14
n-C7H14
isooctane
T (°C) Time (min) Conv. (%) Yield (%) a
1
2
TfOH (3 eq.)
TfOH (3 eq.)
80
60
30
10
180
180
240
120
240
120
180
100
100
100
100
100
-
100
96
110
150
180
150
180
250
250
25
3
TfOH (3 eq.)
trace b
40
4
5
6
7
8
9
10
Tb(OTf)3 (10)
Tb(OTf)3 (10)
Tb(OTf)3 (10)
Tb(OTf)3 (20)
Tb(OTf)3 (10)
TfOH-SiO2(30 )
TfOH-SiO2 (30)
86 c
-
18
32
-
45
20
-
CH2Cl2 (dry)
CH2Cl2 (dry)
180
-
-
a Isolated yields; b The high temperature broke the Teflon septum; c Formation of intermolecular Friedel-craft
acylation by-products.
Scheme 2. MW-, US-assisted and Q-tube™ protocols for 1-indanone synthesis applied to
several aryl-3-propionic acids.
O
TfOH 10 eq, dry CH2Cl2
R4
US, 40 °C
OH
TfOH 3 eq, dry CH2Cl2
MW, 80 °C
TfOH 3 eq, dry CH2Cl2
R3
R1
R
Q-tube, 80 °C
O
R2
R1=R2=R4=H
R1=R3=R4=H
R2=R3=R4=H
R2=R3=R4=H
R1=R2=H
R3=OMe
R2=OMe
R1=OMe
R1=Me
1a
2a + 2b
3a
4a
1
2
3
4
5a
R =R =OMe
5
2
3
R2=R4=H
6a
7a
8a
9a
R =R =OMe
R3=Br
R1=Br
6
7
8
9
10
11
12
13
14
1
3
R1=R2=R4=H
R2=R3=R4=H
R1=R2=R3=R4=H
R1=R2=R4=H
R1=R3=R4=H
R1=R2=R4=H
R1=R3=H
R3=Me
R2=Me
R3=Cl
R2=R4=Br
R3=NO2
10a
11a + 11b
12a
13a
14a
R1=R2=R4=H
In the case of 3-(2-methoxyphenyl)propionic acid (3), the only available cyclization site is the
non-activated 6-position on the aromatic ring, so that no product formation was observed and only
polymerized products were detected (Table 3, entry 3). Moreover, an unfavorable electronic effect can
be invoked to explain the failure of the intramolecular cyclization in substrate 3. As depicted in Figure 1,
an H-bond can constrain the acidic OH to form a transient stable ring and keep the carboxylic moiety
distant from the aromatic ring. This hypothesis is confirmed by the results observed for 3-(2-
methylphenyl)propionic acid where the absence of the ether oxygen prevents the formation of the
transient ring through the O-H interaction leaving the carboxylic group free to attack the non-activated
6-position on the aromatic ring and furnishing a quantitative yield of the 1-indanone derivative 4a
(Table 3, entry 4).

Molecules 2014, 19
5604
Table 3. MW vs. US method in the intramolecular Friedel-Craft acylation of phenyl
propionic acids 1–7.
US-Assisted Reaction a
MW-Assisted Reaction a Q-Tube-Assisted Reaction a
Entry
Product
Time Conv
Yield
(%)
Time Conv
Yield
(%)
Time Conv
Yield
(%)
(min)
(%)
(min)
(%)
(min)
(%)
150
100
100
100
100
60
100
100
100
100
60
100
100
100
100
1
2
210 b
90 b
90 b
MeO
1a
O
MeO
88/12
90/10
90/10
60
100
100
60
100
100
60
100
100
(2b)/(2a)
(2b)/(2a)
(2b/2a)
O
2a
2b
OMe
O
c
c
c
3
120
-
180
-
180
-
4
5
6
7
60
60
100
100
-
100
100
-
60
60
100
100
-
100
100
-
60
60
100
100
-
100
100
-
MeO
MeO
5a
O
360
360
180
180
180 d
60 e
42
33
180 d
60 e
54
36
100
100
Br
100
100
100
100
7a
O
180 d
60 e
58
48
180 d
60 e
44
43
8
9
1200
60
90
90
100
100
100
100
100
100
100
180
100
100
100
180
100
100
100
9a
O
10
11
12
60
60
100
100
100
60
60
100
100
60
60
100
100
Me
10a
O
Me
85/15
88/12
88/12
O
O
(11b)/(11a)
(11b)/(11a)
(11b)/(11a)
Me
11b
11a
180 d
60 e
38
30
180 d
60 e
45
33
400
100
100
-
Cl
100
100
100
100
12a
Br
O
180 d
120 e
32
28
180 d
120 e
40
36
13
14
460
100
-
100
100
100
100
Br
13a
O
1200 d
360 e
-
-
360 e
-
-
O2N
14a
O
a
1
All new products were characterized by GC/MS and H-NMR spectroscopy; all the known products were
b
characterized by comparison with the spectral data in the literature; Reaction conducted with 5.0 mmol of
reactant; c Formation of poli-ketones by polymerization; d Reaction conducted in presence of 5 eq. of TfOH;
e Reaction conducted in presence of 10 equivalents of TfOH.

Molecules 2014, 19
Figure 1. Proposed unfavourable electronic effect involved in the failure of the
5605
3-(2-methylphenyl)propionic acid 3 intramolecular cyclization.
O
O
O H
Similarly, the unfavourable electronic effect associated with greater steric hindrance can explain the
extremely poor reactivity in the case of 3-(2,4-dimethoxyphenyl) propionic acid (6) where only the
starting material was recovered in all three reaction systems, even after prolonged reaction times
(Table 3, entry 6). In all the other reported examples quantitative product yields were observed for all
three activation methodologies in very short reaction times and without significant by-product
formation (Table 3, entries 1, 2, 5, 8–13). It is worth noting that the dis-activated halo-substituted
phenylpropionic acids 7, 8, 12 and 13 gave quantitative yields for the direct intramolecular cyclization
which, to the best of our knowledge, has never reported before. However, no conversion was observed
in the case of the highly deactivated 3-(4-nitrophenyl)propionic acid (14) under all the experimental
conditions adopted (Table 3, entry 14), even after very prolonged reaction times and using higher
amounts of catalyst.
Finally, in order to test the scalability of the protocol, a scaled-up reaction was realized on
5.0 mmol of 3-(4-methoxyphenyl)propionic acid (1) (Table 3, entry 1, line 2), giving rise to the same
results in terms of conversion, yield and reaction profile, but after a slightly longer reaction time. All
the synthetic methodologies tested in this work enable much shorter reaction times and use of an
acceptable amount of triflic acid [27]. o-Chlorobenzene was replaced by CH2Cl2 [34]. The comparison
of the three techniques reported in Table 3 shows that MW-assisted reactions could be performed using
only 3 equivalents of triflic acid in shorter reaction times than the other protocols. On the other hand,
US-assistance allows the reaction to be conducted at lower temperature and with a significantly cleaner
profile, simplifying the reaction work-up despite the higher amount of triflic acid required. The
Q-tube™ technology gave the same results as the MW-assisted protocol but with cleaner reaction
profiles, offering a good alternative to MW or US technologies in terms of yield, safety and efficiency.
3. Experimental
3.1. General Information
All chemicals were obtained from Sigma-Aldrich or Acros Organics (Geel, Belgium) and used as
received. All solvents were distilled using standard methods before use. All reactions were carried out
in flame-dried glassware, under a dry nitrogen atmosphere. MW-assisted reactions were performed on
a Synthos 3000 instrument from Anton Paar (Torino, Italy), equipped with a 64MG5 Rotor and an IR
probe used for external temperature control. US-assisted reactions were performed in a high-power
US-bath (19.6 kHz) made by Danacamerini (Torino, Italy). Q-Tube assisted reactions were performed
in a Q-tube™ safe pressure reactor from Q Labtech (distributed by Sigma-Aldrich), equipped with a
cap/sleeve, a pressure adapter (120 psi), a needle adapter/needle, a borosilicate glass tube, a Teflon
septum and a catch bottle. Reactions were monitored using a GC–MS Thermo Fisher Scientific

Molecules 2014, 19
5606
workstation, composed of a Focus GC (Thermo TR, Waltham, MA, USA- 5 ms SQC 15 m × 0.25 mm
ID × 0.25 µm, working on split mode, 1.2 mL/min using He as the carrier gas) and a DSQ II mass
detector. TLC were performed using Kielsegel 60-F264 on aluminium plates, commercially available
from Merck (Darmstadt, Germany). Liquid flash chromatography was performed on a Supelco
VERSA FLASH HTFP station (distributed by Sigma-Aldrich) using silica cartridges commercially
1
available from Supelco. H-NMR spectra were recorded on a Bruker WM 300 instrument (Milano,
Italy) on samples dissolved in CDCl3. Chemical shifts are given in parts per million (ppm) from
tetramethylsilane as the internal standard (0.0 ppm). All products in this report are known and were
13
characterized by standard techniques (1H- and C-NMR, GC/MS) and the data were compared with
those reported in the literature [33,46–48] for identification.
3.2. General US-Assisted Procedure
Trifluoromethane sulfonic acid (10 eq.) was gently added to a cooled (0 °C) solution of a 3-phenyl
propionic acid (0.5 mmol) in dry CH2Cl2 (0.5 mL) in a two-necked round bottom flask. The temperature
was raised to room temperature. The mixture was reacted in a high-power US-bath (19.6 kHz)
at 40 °C. The reaction was monitored by TLC and GC/MS until the reactant disappeared. The mixture
was poured into ice and extracted three times with CH2Cl2. The organic phase collected was dried over
Na2SO4, filtered and concentrated under vacuum. The desired pure product was separated from the
crude by flash chromatography.
3.3. General MW-Assisted Procedure
Trifluoromethanesulfonic acid (3 eq.) was gently added to a cooled (0 °C) solution of a 3-phenyl
propionic acid (0.5 mmol) in dry CH2Cl2 (1.0 mL) in 3 mL glass vial using a Synthos 3000 microwave
oven (Anton-Paar). The temperature was raised to room temperature. Appropriate Teflon and screw
caps were placed on the top of the vial. The mixture was heated in the MW reactor at 80 °C in
“power-controlled mode” for the appropriate time. The reaction was monitored by TLC and GC/MS
until the reactant disappeared. The mixture was poured onto ice and extracted three times with CH2Cl2.
The collected organic phase was dried on Na2SO4, filtered and concentrated under vacuum. The
desired pure product was separated from the crude by flash chromatography.
3.4. General Q-tubetm-Assisted Procedure
Trifluoromethane sulfonic acid (3 eq.) was gently added to a cooled (0 °C) solution of a 3-Phenyl
propionic acid (0.5 mmol) in dry CH2Cl2 (1.0 mL) in a 12 mL Q-tube™ pressure tube, furnished by Q
Labtech. The temperature was raised to room temperature. A Teflon septum was placed on the top of
the tube and the appropriate cap and pressure adapter were used. The mixture was heated in an oil bath
at 80 °C. The reaction was monitored by TLC and GC/MS until the reactant disappeared. The mixture
was poured into ice and extracted three times with CH2Cl2. The organic phase collected was dried on
Na2SO4, filtered and concentrated under vacuum. The desired pure product was separated from the
crude by flash chromatography.

Molecules 2014, 19
5607
4. Conclusions
We have reported the application of three different non-conventional techniques to the synthesis of
a library of substituted 1-indanones, via the direct Friedel-Crafts intramolecular cyclization of
arylpropionic acids. The comparison between three alternative reaction methodologies, namely MW,
US and Q-Tube™ assisted reactions, showed that Q-tube™ equipment can be proposed as a valid
alternative to monomode MW and US technologies in term of efficiency, safety (virtually eliminating
the risk of pressure explosions) and a cleaner reaction profile.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/5/5599/s1.
Acknowledgments
This study was supported by the following grants: PON a3_00359 CUP F61D11000120007
“Potenziamento Strutturale”.
Author Contributions
The main part of this work was realized by Manuela Oliverio (planning, synthesis and purification
of products) with the practical contribution of Paola Costanzo and Luca Cariati. Monica Nardi
performed compound characterization, while Salvatore Vincenzo Giofrè contributed to the theoretical
choice of indanone moieties. Giancarlo Cravotto contributed on setting US-reactor conditions. The
whole work was coordinated and written by Antonio Procopio.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice; Oxford University Press:
Oxford, UK, 1998.
2. Gawande, M.B.; Bonifácio, V.D.B.; Luque, R.; Branco, P.S.; Varma, R.S. Benign by design:
Catalyst-free in-water, on-water green chemical methodologies in organic synthesis. Chem. Soc. Rev.
2013, 42, 5522–5551.
3. Wu, C.; Nakamura, H.; Murai, A.; Inouye, S. Chemical studies on the chiral indanone derivatives
as the inhibitor of Renilla luciferase. Tetrahedron 2001, 57, 9575–9583.
4. Kerr, D.J.; Hamel, E.; Jung, M.K.; Flynn, B.L. The concise synthesis of chalcone, indanone and
indenone analogues of combretastatin A4. Bioorg. Med. Chem. 2007, 15, 3290–3298.
5. Bansal, R.; Narang, G.; Zimmer, C.; Hartmann, R.W. Synthesis of some imidazolyl-substituted
2-benzylidene indanone derivatives as potent aromatase inhibitors for breast cancer therapy.
Med. Chem. Res. 2011, 20, 661–669.

Molecules 2014, 19
5608
6. Byrne, A.J.; Barlow, J.W.; Walsh, J.J. Synthesis and pharmacological evaluation of the individual
stereoisomers of 3-[methyl(1,2,3,4-tetrahydro-2-naphthalenyl)amino]-1-indanone, a potent mast
cell stabilising agent. Bioorg. Med. Chem. Lett. 2011, 21, 1191–1194.
7. Saxena, H.O.; Faridi, U.; Srivastava, S.; Kumar, J.K.; Darokar, M.P.; Luqman, S.; Chanotiya, C.S.;
Krishna, V.; Negi, A.S.; Khanuja, S.P.S. Gallic acid-based indanone derivatives as anticancer
agents. Biorg. Med. Chem. Lett. 2008, 18, 3914–3918.
8. Schumann, H.; Stenzel, O.; Girgsdies, F. (–)-2-Menthylindenyl and (–)-2-menthyl-4,7-
dimethylindenyl complexes of rhodium, iridium, cobalt, and molybdenum. Organometallics 2001,
20, 1743–1751.
9. Herzog, M.N.; Chien, J.C.W.; Rausch, M.D. Novel 2-indenyl ansa-zirconocenes for the
polymerization of α-olefins. J. Organomet. Chem. 2002, 654, 29–35.
10. Leoni, L.M.; Hamel, E.; Genini, D.; Shih, H.; Carrera, C.J.; Cottam, H.M.; Carson, D.A.
Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug-
resistantm cancer cells. J. Natl. Cancer Inst. 2000, 92, 217–224.
11. Beukes, D.R.; Davies-Coleman, M.T.; Kelly-Borges, M.; Harper, M.K.; Faulkner, D.J.;
Dilemmaones, A.-C. Dilemmaones A−C, unusual indole alkaloids from a mixed collection of
South African Sponges. J. Nat. Prod. 1998, 61, 699–701.
12. Pellissier, H. Recent developments in the Nazarov process. Tetrahedron 2005, 61, 6479–6517.
13. Frontier, A.J.; Collinson, C. The Nazarov cyclization in organic synthesis. Recent advances.
Tetrahedron 2005, 61, 7577–7606.
14. Coyanis, E.M.; Panayides, J.L.; Fernandes, M.A.; de Koning, C.B.; van Ottoerlo, W.A.L.
Ring-closing metathesis for the synthesis of substituted indenols, indenones, indanones and
indenes: Tandem RCM-dehydrogenative oxidation and RCM-formal redox isomerization.
J. Organomet. Chem. 2006, 691, 5222–5224.
15. Clark, W.M.; Tickner-Eldridge, A.M.; Huang, G.K.; Pridgen, L.N.; Olsen, M.A.; Mills, R.J.;
Lantos, I.; Baine, N.H. A catalytic enantioselective synthesis of the endothelin receptor
antagonists SB-209670 and SB-217242. A base-catalyzed stereospecific formal 1,3-hydrogen
transfer of a chiral 3-arylindenol. J. Am. Chem. Soc. 1998, 120, 4550–4551.
16. Wang, G.; Zheng, C.; Zhao, G. Asymmetric reduction of substituted indanones and tetralones
catalyzed by chiral dendrimer and its application to the synthesis of (+)-sertraline. Tetrahedron:
Asymmetry 2006, 17, 2074–2081.
17. Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T. Enantioselective synthesis of 2-hydroxy-1-
indanone, a key precursor of enantiomerically pure 1-amino-2-indanol. Tetrahedron: Asymmetry
1998, 9, 907–910.
18. Torisawa, Y.; Aki, S.; Minamikawa, J. Conversion of indanone oximes into isocarbostyrils.
Bioorg. Med. Chem. Lett. 2007, 17, 453–455.
19. Yadav, J.S.; Reddy, G.S.K.K.; Sabitha, G.; Krishna, A.D.; Prasad, A.R.; Rahaman, H.R.R.;
Rao, K.V.; Rao, A.B. Daucus carota and baker’s yeast mediated bio-reduction of prochiral
ketones. Tetrahedron: Asymmetry 2007, 18, 717–723.
20. Sharma, A.K.; Subramani, A.V.; Gorman, C.B. Efficient synthesis of halo indanones via
chlorosulfonic acid mediated Friedel-Crafts cyclization of aryl propionic acids and their use in
alkylation reactions. Tetrahedron 2007, 63, 389–395.

Molecules 2014, 19
5609
21. Fukuoka, M.; Yoshihira, K.; Natori, S.; Mihashi, K.; Nishi, M. Carbon-13 nuclear magnetic
resonance spectra of pterosin-sesquiterpenes and related indan-1-one derivatives. Chem. Pharm. Bull.
1983, 31, 3113–3128.
22. Sugimoto, H. Structure-activity relationships of acetylcholinesterase inhibitors: Donepezil
hydrochloride for the treatment of Alzheimer’s Disease. Pure Appl. Chem. 1999, 71, 2031–2037.
23. Bhattacharya, A.; Segmuller, B.; Ybarra, A. Preparation of acrylophenones and 2-alkyl indanones
utilizing hexamethylenetetramine as an inexpensive mannich reagent. Synth. Commun. 1996, 26,
1775–1784.
24. De Castro, C.; Primo, J.; Corma, A. Heteropolyacids and large-pore zeolites as catalysts
in acylation reactions using α,β-unsaturated organic acids as acylating agents. J. Mol. Catal.
A-Chem. 1998, 134, 215–222.
25. Gevorgyan, V.; Quan, L.G.; Yamamoto, Y. Synthesis of indenols and indanones via catalytic
cyclic vinylpalladation of aromatic aldehydes. Tetrahedron Lett. 1999, 40, 4089–4092.
26. Rudler, H.; Denise, B. Copper(II)-catalyzed aerobic oxidation of indane in the presence of
aldehydes: Intermediate formation of hydroperoxides. J. Mol. Catal. A-Chem. 2000, 154, 277–279.
27. Prakash, G.K.S.; Yan, P.; Torok, B.; Olah, G.A. Gallium(III) trifluoro-methanesulfonate: A Water
tolerant, reusable lewis acid catalyst for Friedel-Crafts reactions. Catal. Lett. 2003, 87, 109–112.
28. Gagnier, S.V.; Larock, R.C. Palladium-catalyzed carbonylative cyclization of unsaturated aryl
iodides and dienyl triflates, iodides, and bromides to indanones and 2-cyclopentenones. J. Am.
Chem. Soc. 2003, 125, 4804–4807.
29. Fillion, E.; Fishlock, D. Convenient access to polysubstituted 1-indanones by Sc(OTf)3-Catalyzed
intramolecular Friedel-Crafts acylation of benzyl meldrum’s acid derivatives. Org. Lett. 2003, 5,
4653–4656.
30. Johnson, W.S. The formation of cyclic ketones by intramolecular acylation. Org. React. 1949, 2,
114–177.
31. Popp, F.D.; McEwen, W.E. Polyphosphoric acids as a reagent in organic chemistry. Chem. Rev.
1958, 58, 321–401.
32. Miller, R.B.; Frincke, J.M. Stereospecific total synthesis of (.+-.)-vetiselinenol. J. Org. Chem.
1981, 46, 2972–2974.
33. Eaton, P.E.; Carlson, G.R.; Lee, J.T. Phosphorus pentoxide-methanesulfonic acid. Convenient
alternative to polyphosphoric acid. J. Org. Chem. 1973, 38, 4071–4073.
34. Cui, D.M.; Zhang, C.; Kawamura, M.; Shimada, S. Synthesis of 1-indanones by intramolecular
Friedel-Crafts reaction of 3-arylpropionic acids catalyzed by Tb(OTf)3. Tetrahedron Lett.2004,
45, 1741–1745.
35. Mason, T.J. Ultrasound in synthetic organic chemistry. Chem. Soc. Rev. 1997, 26, 443–451.
36. Cravotto, G.; Nano, G.M.; Palmisano, G.; Tagliapietra, S.; Demetri, A.; Penoni, A. The aldol
reaction under high-intensity ultrasound: A novel approach to an old reaction. Eur. J. Org. Chem.
2003, 22, 4438–4444.
37. Kappe, C.O.; Dallinger, D.; Murphree, S.S. Practical Microwave Synthesis for Organic Chemists,
1st ed.; Wiley-VCH: Weinheim, Germany, 2009.
38. Kappe, C.O. Controlled microwave heating in modern organic synthesis. Angew. Chem. Int. Ed.
2004, 43, 6250–6284.

Molecules 2014, 19
5610
39. Procopio, A.; Gaspari, M.; Nardi, M.; Oliverio, M.; Tagarelli, A.; Sindona, G. Simple and
efficient MW-assisted cleavage of acetals and ketals in pure water. Tetrahedron. Lett. 2007, 48,
8623–8627.
40. Procopio, A.; de Luca, G.; Nardi, M.; Oliverio, M.; Paonessa, R. General MW-assisted grafting of
MCM-41: Study of the dependence on time dielectric heating and solvent. Green Chem. 2009, 11,
770–773.
41. Procopio, A.; Costanzo, P.; Dalpozzo, R.; Maiuolo, L.; Nardi, M.; Oliverio, M. Efficient ring
opening of epoxides with trimethylsilyl azide and cyanide catalyzed by erbium (III) triflate.
Tetrahedron Lett. 2010, 51, 5150–5153.
42. Procopio, A.; Cravotto, G.; Oliverio, M.; Costanzo, P.; Nardi, M.; Paonessa, R. An eco-sustainable
erbium(III)-catalysed method for formation/cleavage of O-tert-butoxy carbonates. Green Chem.
2011, 13, 436–443.
43. Nardi, M.; Cozza, A.; Maiuolo, L.; Oliverio, M.; Procopio, A. 1,5-Benzoheteroazepines through
eco-friendly general condensation reactions. Tetrahedron Lett. 2011, 52, 4827–4834.
44. Cravotto, G.; Procopio, A.; Oliverio, M.; Orio, L.; Carnaroglio, D. Simple sonochemical protocols
for fast and repeatable Grignard reactions. Green Chem. 2011, 13, 2806–2809.
45. Liu, P.N.; Xia, F.; Wang, Q.W.; Ren, Y.J.; Chen, J.Q. Triflic acid adsorbed on silica gel as an
efficient and recyclable catalyst for the addition of β-dicarbonyl compounds to alcohols and
alkenes. Green Chem. 2010, 12, 1049–1055.
46. Duddeck, H.; Toth, G.; Simon, A. Chemical Shifts for Oxygen-Springer; Verlag Berlin:
Heidelberg, Germany, 2002.
47. Gomez-Lor, B.; Frutos, O.D.; Ceballos, P.A.; Granier, T.; Echavarren, A.M. Synthesis of new C3h
and C3v Truxene derivatives. Eur. J. Org. Chem. 2001, 11, 2107–2114.
48. Takeuchi, R.; Yasue, H. Rhodium complex-catalyzed desilylative cyclocarbonylation of 1-aryl-2-
(trimethylsilyl)acetylenes: A new route to 2,3-dihydro-1H-inden-1-ones. J. Org. Chem. 1993, 58,
5386–5392.
Sample Availability: Samples of the compounds are available from the authors.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).