A simple conversion of azlactones into indenones via H3PW 12O40/Al2O3 catalyzed intramolecular Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tetlet.2011.10.120

A rapid and simple procedure for the synthesis of the indenone derivatives, N-(1-oxo-1H-inden-2-yl)benzamides, via intramolecular Friedel-Crafts (IFC) reaction of (Z)-4-arylidene-2-phenyl-5(4)-oxazolones (azlactones) catalyzed by H₃PW₁₂

Full text of DOI:10.1016/j.tetlet.2011.10.120

Tetrahedron Letters 52 (2011) 7149–7152
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple conversion of azlactones into indenones via H3PW12O40/Al2O3
catalyzed intramolecular Friedel–Crafts reaction
⇑
⇑
Mahboubeh Rostami, Ahmad R. Khosropour , Valiollah Mirkhani , Majid Moghadam,
Shahram Tangestaninejad, Iraj Mohammadpoor-Baltork
Catalysis Division, Department of Chemistry, Faculty of Science, University of Isfahan, Isfahan 81746-7344, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2011
Revised 2 October 2011
Accepted 21 October 2011
Available online 28 October 2011
A rapid and simple procedure for the synthesis of the indenone derivatives, N-(1-oxo-1H-inden-2-yl)-
benzamides, via intramolecular Friedel–Crafts (IFC) reaction of (Z)-4-arylidene-2-phenyl-5(4)-oxazolones
(azlactones) catalyzed by H3PW12O40 supported on neutral alumina under microwave irradiation has
been developed. The reaction is straightforward and allows easy isolation of the product. The catalyst
could be re-used up to four times after simple filtration.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indenones
Azlactones
Intramolecular Friedel–Crafts reaction
Microwave irradiation
H3PW12O40/Al2O3
The demand for increasingly clean and efficient chemical syn-
theses is important from both economic and environmental points
of view. Solid-state organic reactions have gained importance in
organic synthesis due to several advantages including faster reac-
tions, selectivities different from those in solution, and greener
procedures.1 Nonetheless, the long reaction times, which are fre-
quently required for full conversions have limited the exploitation
of these reactions in high-throughput synthesis. In recent years,
investigation on organic synthesis via microwave-assisted meth-
ods has gained importance.2 Clean reactions, short reaction times,
simple procedures, increased selectivities, and high yields are
advantageous features of MW-assisted methods.3
Recently, applications of heteropoly acids (HPAs) in chemistry
have increased significantly.4 Among HPAs, H3PW12O40, owing to
its stronger acidity (Brønsted acid) and higher thermal stability
compared to other examples, is usually the catalyst of choice.5 Fur-
thermore, modification of the activity of H3PW12O40 has been
accomplished by supporting it on a solid such as alumina.6
The presence of the indenone skeleton in a number of naturally
occurring compounds and synthetic materials, with important bio-
logical properties, illustrates the need for the development of new
methods for the preparation of these compounds. For instance,
euplectin, a rare natural product with an indenone moiety, was re-
ported to exhibit cytotoxicity against the growth of murine P-815
mastocytoma cells.7 Some indenone derivatives are used as impor-
tant starting materials for the synthesis of kinamycin antibiotics,
which show excellent activity against Gram-positive bacteria.8
On the other hand, increased effort has been directed toward the
development of new indenone-based structures as ligands in orga-
nometallic chemistry.9
The intramolecular Friedel–Crafts (IFC) reaction is an attractive
method for the formation of these types of compounds. This method
was established by Awad et al. for the synthesis of 2-benzamidoin-
denone in the presence of AlCl3 in anhydrous carbon tetrachloride.10
Recently, this transformation was modified by Kangani et al.
through IFC reaction of 2-benzylamino-3-phenylacrylic acid using
cyanuric chloride, pyridine, and AlCl3.11 However, one of the chal-
lenging problems in such processes is the introduction of appropri-
ate substituents during cyclization because, in some cases, the
presence of functional groups often hinders the desired IFC reaction.
Therefore, to overcome these problems, more convenient methods
for the synthesis of these types of compounds are required.
R2
R1
O
R3
R1
R2
O
H3PW12O40/Al2O3
MW
O
N
R4
R4
NH
R3
Ph
O
Ph
⇑
Corresponding authors. Tel./fax: +98 311 668 9732.
E-mail address: khosropour@chem.ui.ac.ir (A.R. Khosropour).
Scheme 1. IFC reaction of azlactones to afford indenones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.120

7150
M. Rostami et al. / Tetrahedron Letters 52 (2011) 7149–7152
In continuation of our recent studies on azlactone chemistry,12
Table 1
Optimization of the IFC reaction of 1c to give 2c
and as a part of our ongoing research program to develop new
methodologies for the synthesis of fine chemicals,13 herein we de-
scribe the successful use of H3PW12O40 supported on neutral alu-
mina14 as an active catalyst for the synthesis of N-(1-oxo-1H-
inden-2-yl)benzamides via IFC reaction of azlactones under micro-
wave irradiation (Scheme 1).15
Br
O
O
H3PW12O40/Al2O3
O
N
Br
MW, 30 min
NH
In order to optimize the reaction conditions, the IFC reaction of
Ph
O
Ph
(Z)-4-(4-bromobenzylidene)-2-phenyloxazol-5(4H)-one
(1c,
2c
1c
1 mmol) in the presence of H3PW12O40/Al2O3 (250 mg) was se-
lected as a model reaction (Table 1). We investigated the reaction
under microwave irradiation with a temperature controlled pro-
gram. During irradiation, the temperature was monitored by an
IR sensor which controlled the MW power levels.
Optimization by screening the reaction conditions including the
amount of the catalyst, temperature and output power of the
microwave irradiation was investigated. The results indicated that
lower amounts of catalyst gave lower yields (Table 1, entries 1 and
2). The reactions were carried out at temperatures ranging from 90
to 120 °C. It was found that a higher reaction temperature (120 °C)
led to no improvement in the yield, but using a lower temperature
(100 °C), sharply decreased the conversion to 73%. The procedure
was carried out at different microwave irradiation output power
(Table 1, entries 3, 8, and 9). It was found that the yield reached
a plateau at 650 W (Table 1, entry 3).
Entry Catalyst
(mg)
Solvent
Power
(W)
Temperature
Yield
(%)a
(°C)
1
2
3
4
5
6
7
8
9
150
200
250
300
250
250
250
250
250
250
250
250
250
—
—
—
—
—
—
—
—
650
650
650
650
650
650
650
550
750
—
115
115
115
115
90
100
120
115
115
115
80
79
83
86
87
66
73
85
70
88
—
—
—
10b
11
12
13
CH3CNc
EtOHc
PEG-
400c
650
650
650
46
42
65
78
115
a
b
C
Isolated yield.
Under oil bath heating.
Two milliliters of solvent.
To demonstrate the positive effect of MW irradiation, the syn-
thesis of 2c was investigated with and without microwave irradia-
tion. When the reaction was carried out in the absence of
Table 2
Synthesis of N-(1-oxo-1H-inden-2-yl)benzamides via IFC-reaction of azlactones catalyzed by H3PW12O40/Al2O3 (see Scheme 1)
Entry
R1
R2
R3
R4
Product
Time (min)
40
Yield (%)a
8616
O
O
Cl
1
H
Cl
H
H
2a
2b
NHCOPh
NHCOPh
Cl
2
H
Cl
H
Cl
45
81
Cl
O
Br
3
4
H
Br
H
H
H
H
H
2c
40
40
87
85
NHCOPh
Br
O
Br
2d
NHCOPh
O
O2N
5
6
7
H
H
H
NO2
H
H
H
H
H
H
2e
2f
42
35
35
83
88
80
NHCOPh
O
H3CO
(H3C)2N
CH3O
(CH3)2N
NHCOPh
O
2g
NHCOPh
OCH3
O
HO
8
CH3O
HO
CH3O
H
2h
40
81
NHCOPh
H3CO

M. Rostami et al. / Tetrahedron Letters 52 (2011) 7149–7152
7151
Table 2 (continued)
Entry
R1
R2
R3
R4
Product
Time (min)
39
Yield (%)a
O
O
O
O
NHCOPh
NHCOPh
9
2i
2j
85
N
O
O
H
N
10
11
40
38
8416
N
N
H
O
O
O
H3C
NHCOPh
2k
8616
S
N
S
H3C
O
o
O
O
PhOCHN
NHCOPh
N
O
N
12
2l
42
8016
O
Yield refers to isolated pure product characterized by FTIR, 1H NMR,13C NMR and mass spectroscopy.
a
+
O
H
O
H
O
NHCOPh
IFC-reaction
H
+
O
N
O
N
Ph
Ph
A
H
= H3PW12O40/Al2O3
Scheme 2. Proposed mechanism.
microwave irradiation with stirring at 115 °C, 2c was not produced
at all (Table 1, entry 10), while at the same temperature under
microwave irradiation, a high yield of the corresponding product
was obtained (86%, Table 1, entry 3). The effect of solvent on this
transformation was also investigated. As shown in Table 1, the de-
sired product was obtained in unsatisfactory conversion in acetoni-
trile, ethanol, and PEG-400 (46%, 42%, and 65%, respectively). Thus
the optimum conditions required solvent-free microwave irradia-
tion at 115 °C and 650 Watt power for the IFC reaction of azlac-
tones to give the corresponding indenones in the presence of
H3PW12O40/Al2O3.
5(4H)-one (1i), (Z)-4-[(1H-indol-3-yl)methylene]-2-phenyloxazol-
5(4H)-one (1j), or (Z)-4-[(5-methylthien-2-yl)methylene]-2-
phenyloxazol-5(4H)-one (1k),12d were reactive substrates and pro-
vided the desired products in satisfactory yields. A particularly
noteworthy feature of the present protocol is the successful synthe-
sis of 2l from (4Z,40Z)-4,40-[1,4-phenylenebis(methan-1-yl-1-
ylidene)]bis(2-phenyloxazol-5(4H)-one12d (1l). The wide potential
of this method makes it an attractive strategy for the synthesis of
N-(1-oxo-1H-inden-2-yl)benzamides.
Another advantage of this method is the recyclability of the cat-
alyst. H3PW12O40/Al2O3 can be separated by simple filtration,
washing with ethanol, and drying at 80 °C under reduced pressure
and reused for at least four runs without any loss of activity.
A plausible mechanism for the formation of N-(1-oxo-1H-in-
den-2-yl)benzamides is shown in Scheme 2. Initially, tautomerism
After successful generation of 2c, we next introduced greater
diversity to the N-(1-oxo-1H-inden-2-yl)benzamide scaffold
(Table 2).
As shown in Table 2, it is clear that using the optimized reaction
conditions, this procedure was quite general. In most cases, the
reaction proceeded with high efficiency and with broad functional
group tolerance. To expand the scope of the azlactone substrates,
various mono and disubstituted azlactones containing both elec-
tron-withdrawing and electron-donating substituents were used,
and these displayed good reactivity and afforded the desired
products in high yields. In addition, polycyclic or heterocyclic azlac-
tones, such as (Z)-4-(naphthalen-1-ylmethylene)-2-phenyloxazol-
of the (Z)-azlactone into (E)-isomer A is catalyzed by H3PW12O40
/
Al2O3. Subsequently, A undergoes the intramolecular Friedel–
Crafts reaction followed by rearrangement into amide.
In conclusion, we have demonstrated a simple and facile syn-
thesis of N-(1-oxo-1H-inden-2-yl)benzamides from azlactones in
the presence of H3PW12O40/Al2O3 under microwave irradiation.
The process is simple and has been shown to generate a diverse
range of indenones in high yields. The experimental simplicity,

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M. Rostami et al. / Tetrahedron Letters 52 (2011) 7149–7152
14. Fazaeli, R.; Tangestaninejad, S.; Aliyan, H.; Moghadam, M. Appl. Catal A. Gen.
2006, 309, 44–51.
15. Typical procedure for the synthesis of N-(6-chloro-1-oxo-1H-inden-2-
ease of product isolation, reusability of the catalyst and ready
availability of the catalyst could make this process very useful for
the synthesis of N-(1-oxo-1H-inden-2-yl)benzamides.
yl)benzamide (2a): In
a high pressure Teflon reactor equipped with a
magnetic stir bar and an IR sensor (for controlling the reaction temperature),
(Z)-4-(4-chlorobenzylidene)-2-phenyloxazol-5(4H)-one (0.283 g, 1 mmol) and
H3PW12O40/Al2O3 (0.250 g, 5.2 mol %) were submitted to microwave
irradiation at 115 °C (650 W) using a micro-SYNTH lab station reactor for
40 min. During this time, the power was modulated automatically to hold the
reaction temperature at 115 °C. After the reaction was complete (monitored by
TLC), the mixture was cooled to room temperature, filtered, washed with a hot
mixture of EtOAc–EtOH (10:1, 2 ꢀ 10 ml), and concentrated in vacuo to give a
crude residue, which was purified as appropriate by recrystallisation from
EtOH.
Acknowledgments
The authors are grateful to the Center of Excellence of Chemis-
try and the Research Council of the University of Isfahan for finan-
cial support of this work.
References and notes
16. Selected spectral data for 2a, 2j, 2k and 2l: N-(6-chloro-1-oxo-1H-inden-2-
yl)benzamide (2a): FTIR (KBr, solid): 3235, 1698, 1644, 1470, 1423, 1311, 1277,
1088, 910, 699, 524. 1H NMR (500 MHz, DMSO-d6): d = 9.54 (s, 1H), 7.88–7.89
(d, J = 7.55 Hz, 2H), 7.54–7.56 (t, J = 7.8 Hz, 1H), 7.47–7.50 (t, J = 7.8 Hz, 2H),
7.34–7.35 (d, J = 8.1 Hz, 1H), 7.28–7.29 (d, J = 8.1 Hz, 2H), 7.16 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d = 167.6, 163.5, 149.5, 137.1, 135.8, 134.7, 131.4, 130.9,
130.4, 128.4, 127.6, 127.3, 124.2, 122.9. MS (EI): m/z 285.32 [M+2], 283.74
[M]+, 149.94, 104.87, 76.86, 50.9. N-(3,4-Dihydro-3-oxocyclopenta[b]indol-2-
yl)benzamide (2j): FTIR (KBr, solid): 3364, 3343, 1698, 1644, 1539, 1079, 962,
889, 792, 437. 1H NMR (300 MHz, DMSO-d6): d = 10.31 (s, 1H), 9.98 (s, 1H),
7.83–7.85 (d, J = 5.58 Hz, 2H), 7.65 (br s, 3H), 7.48–7.49 (d, J = 4.4 Hz, 2H), 7.40–
7.43 (t, J = 4.7 Hz, 2H), 7.3 (s, 1H). 13C NMR (125 MHz, DMSO-d6): d = 166.15,
163.73, 149.35, 137.98, 133.48, 133.18, 131.76, 131.47, 131.46, 130.97, 130.84,
128.41, 128.22, 127.63, 122.29, 117.99. MS (EI): m/z 167.07 [M-120], 149, 71,
57. N-(2-methyl-4-oxo-4H-cyclopenta[b]thiophen-5-yl)benzamide (2k): FTIR
(KBr, solid): 3395, 1695, 1610, 1539, 1448, 1028, 670, 469. 1H NMR
(400 MHz, DMSO-d6): d = 9.3 (s, 1H), 7.99 (s, 2H), 7.33–7.68 (m, 3H), 7.01 (s,
1H), 6.71 (s, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, DMSO-d6): d = 166.09,
163.80, 149.89, 144.12, 141.57, 135.82, 130.91, 130.4, 128.46, 127.65, 127.32,
121.99, 17.21. MS (EI): m/z 148.96 [Mꢁ120], 104.94, 76.95, 57.04. N,N0-(1,5-
Dioxo-1,5-dihydros-indacene-2,6-diyl)dibenzamide (2l): FTIR (KBr, solid): 3374,
1703, 1610, 1569, 1437, 1266, 1026, 675, 589. 1H NMR (400 MHz, DMSO-d6):
d = 9.7 (s, 2H), 7.94–7.95 (d, J = 7.1 Hz, 2H), 7.84–7.85 (d, J = 7.1 Hz, 2H), 7.66
(br s, 2H), 7.49–7.51 (t, J = 8.4 Hz, 4H), 7.41–7.44 (t, J = 8.35 Hz, 4H). 13C NMR
(125 MHz, DMSO-d6): d = 167.01, 165.93, 152.17, 142.38, 133.22, 131.76,
131.48, 128.41, 127.63, 126.40, 121.48. MS (EI): m/z 420.19 [M]+, 105.01,
77.02, 55.04.
1. Desiraju, G. R. Organic Solid State Chemistry; Elsevier: Amsterdam, 1987.
2. (a) Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2010, 39,
1467–1477; (b) Martinez-Palou, R. Mol. Diversity 2010, 14, 3–25.
3. (a) Strauss, C. R.; Rooney, D. W. Green Chem. 2010, 12, 1340–1344; (b) Haque,
E.; Khan, N. A.; Park, J. H.; Jhung, S. H. Chem. Eur. J. 2010, 16, 1046–1052.
4. (a) Kozhevnikov, I. V. Catalysts for Fine Chemical Synthesis. Catalysis by
Polyoxometalates; Wiley & Sons: Chichester, 2002; (b) Costa, V. V.; Rocha, K.
A. S.; Kozhevnikov, I. V.; Gusevskaya, E. V. Appl. Catal. A 2010, 383, 217–220.
5. Kozhevnikov, I. V. J. Mol. Catal. A 2009, 305, 104–111.
6. Kim, P.; Kim, H.; Yi, J.; Song, I. K. Stud. Surf. Sci. Catal. 2006, 159, 265–268.
7. Ernst-Russell, M. A.; Chai, C. L. L.; Wardlaw, J. H.; Elix, J. A. J. Nat. Prod. 2000, 63,
129–131.
8. Kitani, Y.; Morita, A.; Kumamoto, T.; Ishikawa, T. Helv. Chim. Acta 2002, 85,
1186–1195.
9. Kim, D. H.; Son, S. U.; Chung, Y. K. Org. Lett. 2003, 5, 3151–3153.
10. Awad, W. I.; Hafez, M. S. J. Org. Chem. 1961, 26, 2055–2057.
11. Kangani, C. O.; Day, B. W. Org. Lett. 2008, 10, 2645–2648.
12. (a) Khodaei, M. M.; Khosropour, A. R.; Jomor, S. J. H. J. Chem. Res., Synop. 2003,
638–641; (b) Khosropour, A. R.; Khodaei, M. M.; Jomor, S. J. H. J. Heterocycl.
Chem. 2008, 45, 683–686; (c) Rostami, M.; Khosropour, A. R.; Mirkhani, V.;
Moghadam, M.; Tangestaninejad, S.; Mohammadpoor-Baltork, I. Appl. Catal., A
Gen. 2011, 397, 27–34; (d) Rostami, M.; Khosropour, A. R.; Mirkhani, V.;
Moghadam, M.; Tangestaninejad, S.; Mohammadpoor-Baltork, I. C. R. Chimi.
2011, 14, 869–877.
13. Khorsandi, Z.; Khosropour, A. R.; Mirkhani, V.; Mohammadpoor-Baltork, I.;
Moghadam, M.; Tangestaninejad, S. Tetrahedron Lett. 2011, 52, 1213–1216.