One-step synthesis of indanones through NbCl5-induced Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tetlet.2015.06.061

Abstract This Letter describes the use of NbCl₅ as the Lewis acid in Friedel-Crafts reactions, in which a bifunctional electrophile reacts inter- and intramolecularly with an aromatic ring to produce a number of indanones in a single step, main

Full text of DOI:10.1016/j.tetlet.2015.06.061

Tetrahedron Letters 56 (2015) 4649–4652
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-step synthesis of indanones through NbCl5-induced
Friedel–Crafts reaction
⇑
Jader da Silva Barbosa , Gil Valdo José da Silva, Mauricio Gomes Constantino
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, 14040-901 Ribeirão Preto, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the use of NbCl5 as the Lewis acid in Friedel–Crafts reactions, in which a bifunctional
electrophile reacts inter- and intramolecularly with an aromatic ring to produce a number of indanones
in a single step, maintaining mild conditions and good yields.
Received 2 April 2015
Revised 12 June 2015
Accepted 22 June 2015
Available online 26 June 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis of 1-indanone
Friedel–Crafts
Cycliacylalkylation
Niobium pentachloride
Lewis acid
Introduction
Ph
O
Cl
O
OH
N
N
OH
Cl
H
N
Ph
Me
N
O
The Friedel–Crafts reaction is an important method for carbon–
carbon bond formation in which one of the reactants is an aromatic
compound. This method is specially useful for the synthesis of cyc-
lic aromatic ketones such as indanones and other classes of impor-
tant compounds.1 The intramolecular Friedel–Crafts acylation is
known in the literature to proceed in high yield,2,3 but the
Friedel–Crafts cyclization, in which bifunctional electrophiles react
inter- and intramolecularly with an aromatic ring, is more difficult
to perform, mainly because intermolecular competition can reduce
the possibility of cyclization.3
The indane ring is commonly found in a number of drugs and
natural products with biological activity, such as IndinavirÒ—an
HIV-protease inhibitor,4 AriceptÒ—used in the treatment of
Alzheimer’s disease,5 the mutisiantol6, and (+)-indacrinone—drug
against hypertension7 (Fig. 1).
In the literature one can find a wide variety of methods to syn-
thesize indanones by a sequence of acylation–arylation (cycliacy-
larylation) Friedel–Crafts reactions, catalyzed by aluminum
chloride, polyphosphoric acid, and phosphotungstic acid, etc.3,8,9
Usually, the reactions present a number of limitations, such as,
low to moderate yields, long reaction times, or the need of severe
conditions, with use of high temperatures and concentrated acids.
Superacid-catalyzed (triflic acid) and H-zeolites directed reactions
t-Bu
HO2
C
O
N
H
(+) Indacrinone
Indinavir®
HO
O
Cl-
MeO
MeO
NH
Aricept®
( )-Mutisiantol
Figure 1. Examples of compounds containing the indane ring.
H3C
CH3
H3C
H3C
CO2H
NbCl5
R
R
2
O
Scheme 1. Outline of the investigated reactions.
have been reported. In the first case, the formation of either inda-
none or chalcone depends on the substitution of the aryl group in
the starting cinnamic acid.10 In the other case, there is a competi-
tion between indanone formation and decarboxyarylation depend-
ing on the zeolite used.11
In this letter we describe our investigation on the synthesis of
indanones in one step, through a double Friedel–Crafts reaction,
⇑
Corresponding author. Tel.: +55 16 3625 2638.
E-mail address: silvajdr@usp.br (J. da Silva Barbosa).
http://dx.doi.org/10.1016/j.tetlet.2015.06.061
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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J. da Silva Barbosa et al. / Tetrahedron Letters 56 (2015) 4649–4652
using an a,b-unsaturated carboxylic acid as bidentate reagent, and
the powerful oxophilic Lewis acid NbCl5 as catalyst12 (Scheme 1).
Since 3,3-dimethylacrylic acid (2) is a non-symmetrical biden-
tate reagent, there are two possible courses for this reaction: (1)
a Friedel–Crafts intermolecular acylation followed by a Friedel–
Crafts intramolecular alkylation, or (2) an intermolecular alkyla-
tion followed by an intramolecular acylation. In general, two or
more products could be expected with substituted aromatic rings
as substrates.
The tandem Friedel–Crafts reaction was performed13 in 5 mL of
anhydrous dichloromethane at three different temperatures; 0 °C,
25 °C, and reflux. The molar ratio was kept constant between 3,3-
dimethylacrylic acid (2) (0.5 mmol) and the aromatic substrate
(1 mmol) (Scheme 1). NbCl5 was used in 1 or 2 mmol and the best
result is reported in Table 1. The products were analyzed by 1H and
13C NMR, IR, and HRESIMS.14
We started our studies using toluene as the aromatic substrate
(Table 1, entry 1), and the indanone 3 was obtained in 78% yield
at 25 °C. We expected that two different regioisomers could be pro-
duced in this reaction, but just one was isolated. To determine the
structure of indanone 3, it was carefully analyzed by NMR, including
a NOEDIFF experiment. The hydrogens in methyl groups attached to
the pentacycle (numbered as 11 and 12 in Fig. 2) of indanone 3 show
NOE correlation with the hydrogen 15 of the aromatic ring, thus
supporting the structure shown here for indanone 3.
Figure 2. NOE correlation found in indanone 3.
reaction was an intermolecular Friedel–Crafts alkylation, followed
by an intramolecular acylation.
Rather surprisingly, with the more reactive aromatic substrate
anisole the first reaction was an acylation, and no cyclization to
form indanones was observed. Product 4 was obtained by the
It is expected that the intermolecular reaction (the first Friedel–
Crafts reaction in the process) should occur in para to the methyl
group of toluene. The structure of 3, thus, suggests that the initial
intermolecular Friedel–Crafts acylation with
a yield of 90%
(Table 1, entry 2). Apparently, the deactivation of the aromatic ring
Table 1
Tandem reactions of toluene, anisole, and xylenes with 3, 3-dimethylacrylic acid (2)
Entry
1
NbCl5 (mmol)
2
Substrate
Toluene
Temp (°C)
Time (min)
Product
Yielda%
O
Reflux
25
50
80
70
78
0
120
25
3
Reflux
25
50
80
72
90
O
2
2
Anisole
0
120
73
O
4
Reflux
25
50
80
38 + 36
38 + 31
O
O
3
4
1
2
o-Xylene
m-Xylene
0
120
37 + 27
5
6
O
Reflux
25
50
80
60 + 5 + 0
28 + 34 + 0
O
0
120
0 + 31 + 34
O
7
8
9
O
p-Xylene
180
Reflux
25
37 + 27
47 + 16
O
5
2
0
45 + 20
10
11
a
Yield of isolated products. All compounds were analyzed by 1H and 13C NMR.

J. da Silva Barbosa et al. / Tetrahedron Letters 56 (2015) 4649–4652
4651
O
sequence, in which case the cyclization leading to indanone always
occurs.
R
Acknowledgments
A
B
Acylated intermediate
CO2H
Indanone
R
+
The authors thank FAPESP, CNPq and CAPES for financial sup-
port and CBMM—Companhia Brasileira de Metalurgia
Mineração for the samples of NbCl5.
e
R
CO2H
Alkylated intermediate
Supplementary data
Scheme 2. Two possible intermediates leading to indanone.
Supplementary data (1H and 13C NMR spectra of the products)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.06.061.
after the initial acylation prevented the cyclization reaction to
occur.
The HSAB principle might explain the difference in behavior
between toluene and anisole regarding the first Friedel–Crafts
reaction: alkylation of toluene and acylation of anisole. Toluene
is a soft nucleophile, but computational investigation shows that
anisole is a hard one.15 In this way, the nucleophile toluene would
References and notes
1. (a) Olah, G. A. Friedel–Crafts Chemistry; John Wiley and Sons: New York, 1973;
(b) Heaney, H. In Comprehensive Organic Synthesis; Pergamon: Oxford, 1991;
vol. 2,; pp 733–753
2. (a) Sass, D. C.; De Lucca, E. C., Jr.; Barbosa, S. J.; Oliveira, K. T.; Constantino, M. G.
Tetrahedron Lett. 2011, 52, 5371; (b) Cui, D.-M.; Zhang, C.; Kawamura, M.;
Shimida, S. Tetrahedron Lett. 2004, 45, 1741; (c) Polo, E. C.; Da Silva-Filho, L. C.;
Silva, G. V. J.; Constantino, M. G. Quim. Nova 2005, 28, 703.
3. Prakash, G. K. S.; Yan, P.; Török, B.; Olah, G. A. Catal. Lett. 2003, 87, 109.
4. Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001, 2203.
5. Sugimoto, H. Pure Appl. Chem. 1999, 71, 2031.
6. Ho, T.-L.; Lee, K.-Y.; Chen, C.-K. J. Org. Chem. 1997, 62, 3365.
7. (a) Jain, A. K.; Michael, R.; Ryan, J. R.; McMahon, F. G. Pharmacotherapy 1984, 4,
278; (b) Dolling, U.-U.; Davis, P.; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106,
446.
8. Hart, R. T.; Tebbe, R. F. J. Am. Chem. Soc. 1950, 72, 3286.
9. Hanessian, S.; Ma, J. Tetrahedron Lett. 2001, 45, 8785.
attack preferably the softer end of the
a,b-unsaturated system,
while anisole would go the other way around, attacking the harder
carbonyl carbon.
With o-xylene at reflux temperature, two isomeric indanones (5
and 6) were formed in about 1:1 ratio with a combined yield of
74%. At lower temperatures the yield of the more hindered inda-
none (6) drops a little, while the yield of (5) remains unaffected.
The absence of non-cyclized products suggests that, as it happened
with toluene, the first reaction was an intermolecular alkylation in
para to one of the methyl groups.
However, with m- and p-xylenes, non-cyclized products (9 and
11) are formed together with indanones. As it happened with ani-
sole, the structures of 9 and 11 leave no doubt that they were
formed by a Friedel–Crafts acylation, which produced a deacti-
vated aromatic ring making the second Friedel–Crafts reaction
more difficult. Note that, with m-xylene, the non-cyclized product
9 was observed only in the reaction at 0 °C, when 7 was absent; at
higher temperatures, compound 9 cyclized to give 7.
The results obtained with p-xylene are not surprising. All the
four positions in the aromatic ring available for substitution are
ortho to one of the methyl groups and meta to the other. They
are thus moderately activated positions and, due to the symmetry
of the substrate, only one indanone can be formed. We found here
a significant amount of non-cyclized product (11) at any reaction
temperature.
Scheme 2 shows the two possible intermediates leading to
indanone. Our results indicate that both pathways actually occur:
an initial alkylation produces an intermediate with activated aro-
matic ring which always leads to indanone formation; on the other
hand, an initial acylation gives an intermediate with deactivated
aromatic ring and sometimes the reaction stops here, without fur-
ther cyclization.
10. Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.; Klumpp, D. A. J. Org. Chem. 2004,
69, 2340.
11. Chassaing, S.; Kumarraja, M.; Pale, P.; Sommer, J. Org. Lett. 2007, 9, 3889.
12. Lacerda Junior, V.; Santos, D. A.; da Silva-Filho, L. C.; Greco, S. J.; Santos, R. B.
Aldrichimica Acta 2012, 45, 19.
13. General procedure: 3,3-dimethylacrylic acid (0.050 g, 0.5 mmol) was added to
a NbCl5 solution (1.0 or 2.0 mmol, see Table 1) in anhydrous dichloromethane
(4.0 mL), under nitrogen atmosphere. A solution of the aromatic substrate
(1.0 mmol) in anhydrous dichloromethane (1.0 mL) was slowly added to the
reaction mixture which was then stirred (temperature and time as
summarized in Table 1). Distilled water (15.0 mL) was then added and
stirring was continued for 30 min. The mixture was filtered and the filtrate was
extracted with dichloromethane (3 Â 15.0 mL). The combined organic layers
were washed with distilled water (2 Â 5 mL) and saturated solution of sodium
chloride (3 Â 5 mL), and dried with anhydrous MgSO4. The solvent was
removed by evaporation. The indanones were isolated by flash column
chromatography on silica gel (hexane/ethyl acetate 7.0:3.0). The yields are
shown in Table 1.
14. 4-Metyl-1-indanone (3): 1H NMR (CDCl3, 500 MHz), d (ppm): 1.40 (s, 6H); 2.40
(s, 3H); 2.58 (s, 2H); 7.38 (d, 1H, J = 7.9 Hz); 7.43 (d, 1H, J = 8.0 Hz); 7.49 (s, 1H).
13C NMR (CDCl3, 125 MHz), d (ppm): 20.95 (CH3), 29.95 (2 CH3), 38.13 (C),
53.16 (CH), 123.15 (CH), 123.18 (CH), 136.11 (2 CH), 135.39 (C), 137.24 (C),
161.30 (C), 206.05 (C@O). IR (KBr, cmÀ1): 1254; 1616; 1718; 2960. HRESINS:
calcd for C13H16O [M+H]+: 175.1123; found 175.1117.
1-(4-Methoxyphenyl)-3-methylbut-2-en-1-one (4): 1H NMR (CDCl3, 400 MHz),
d (ppm): 1.92 (s, 3H); 2.10 (s, 3H); 3.78 (s, 3H); 6.63 (s, 1H); 6.84 (d, 2H,
J = 8.8 Hz); 7.84 (d, 2H, J = 8.8 Hz). 13C NMR (CDCl3, 100 MHz), d (ppm): 21.00,
27.83, 55.36, 113.52, 121.12, 130.40, 132.06, 155.25, 162.87, 190.29. HRESINS:
calcd for C13H16O [M+H]+: 191.1072; found 191.1080.
3,3,5,6-Tetramethyl-1-indanone (5):16 1H NMR (CDCl3, 500 MHz), d (ppm):
1.32 (s, 6H); 2.23 (s, 3H); 2.29 (s, 3H); 2.48 (s, 2H); 7.18 (s, 1H); 7.39 (s, 1H). 13
C
In some cases there are evidences that both pathways occur in
the same reaction. For instance, in the case of m-xylene: the forma-
tion of product 9 shows that some initial acylation has occurred,
while the formation of 8 strongly indicates that an initial alkylation
had occurred, because it would not be reasonable to expect that 8
could be formed through an initial acylation in a position meta to
both methyl groups.
NMR (CDCl3, 125 MHz), d (ppm): 19.71 (CH3), 20.92 (CH3), 30.01 (2 CH3), 38.13
(C), 53.18 (CH2), 123.67 (CH), 124.29 (CH), 133.48 (C), 136.33 (C), 145.16 (C),
152.17 (C), 205.88 (C@O). IR (KBr, cmÀ1): 1600; 1610; 1710; 3006. HRESINS:
calcd for C13H16O [M+H]+: 189.1279 found 189.1281.
3,3,6,7-Tetramethyl-1-indanone (6):16 1H NMR (CDCl3, 500 MHz), d (ppm):
1.37 (s, 6H); 2.30 (s, 3H); 2.56 (s, 2H); 2.59 (s, 3H); 7.20 (s, 1H); 7.35 (s, 1H). 13
C
NMR (CDCl3, 125 MHz), d (ppm): 13.62 (CH3), 18.93 (CH3), 30.15 (2 CH3), 36.81
(C), 53.98 (CH2), 120.22 (CH), 132.65 (C), 135.94 (C), 136.14 (C), 136.82 (C),
162.59 (C), 207.10 (C@O). IR (KBr, cmÀ1): 1605; 1630; 1800; 3006. HRESINS:
calcd for C13H16O [M+H]+: 189.1279 found 189.1280.
Conclusion
3,3,5,7-Tetramethyl-1-indanone (7):16 1H NMR (CDCl3, 500 MHz), d (ppm):
1.36 (s, 6H); 2.38 (s, 3H); 2.53 (s, 2H); 2.57 (s, 3H); 6.90 (s, 1H); 7.07 (s, 1H). 13
C
NMR (CDCl3, 125 MHz), d (ppm): 18.24 (CH3), 21.95 (CH3), 30.04 (2 CH3), 37.45
(C), 53.63 (CH2), 121.23 (CH), 130.35 (CH), 130.55 (C), 138.16 (C), 145.14 (C),
165.17 (C), 206.22 (C@O). IR (KBr, cmÀ1): 1308; 1604; 1698; 2952. HRESINS:
calcd for C13H16O [M+H]+: 189.1279 found 189.1274.
The use of NbCl5 as Lewis acid in a tandem Friedel–Crafts reac-
tion leads to the formation of indanones in only one synthetic step,
with good yields, under mild conditions. Softness of the aromatic
nucleophile favors the alkylation as the first reaction in the
3,3,4,6-Tetramethyl-1-indanone (8):16 1H NMR (CDCl3, 500 MHz), d (ppm):

4652
J. da Silva Barbosa et al. / Tetrahedron Letters 56 (2015) 4649–4652
28.07 (2 CH3), 38.87 (C), 55.38 (CH2), 123.30 (C), 129.70 (CH), 133.50 (C),
1.42 (s, 6H); 2.28 (s, 3H); 2.41 (s, 3H); 2.53 (s, 2H); 7.13 (s, 1H); 7.30 (s, 1H). 13
C
NMR (CDCl3, 125 MHz), d (ppm): 19.43 (CH3), 28.07 (2 CH3), 20.74 (CH3), 39.48
(C), 54.98 (CH2), 121.31 (CH), 135.01 (C), 137.58 (C), 138.88 (CH), 157.43 (C),
206.40 (C@O). IR (KBr, cmÀ1): 1304; 1578; 1712; 2960. HRESINS: calcd for
136.30 (C), 137.00 (CH), 160.54 (C), 217.10 (C@O). IR (KBr, cmÀ1): 1578; 1710;
2958. HRESINS: calcd for C13H16O [M+H]+: 189.1279 found 189.1281.
1-(2,5-Dimethylphenyl)-3-methylbut-2-en-1-one (11): 1H NMR (CDCl3,
400 MHz), d (ppm): 1.90 (s, 3H); 2.10 (s, 3H); 2.26 (s, 2H); 2.34 (s, 3H); 6.36
(s, 1H); 7.02 (d, 1H, J = 7.6 Hz); 7.05 (d, 1H, J = 7.6 Hz), 7.22 (s, 3H). 13C NMR
(CDCl3, 100 MHz), d (ppm): 19.94, 20.93, 27.86, 124.80, 128.66, 131.08, 131.27,
133.77, 135.00, 140.49, 155.56, 196.16. HRESINS: calcd for C13H16O [M+H]+:
189.1279 found 189.1269.
C
13H16O [M+H]+: 189.1279 found 189.1288.
1-(2,4-Dimethylphenyl)-3-methylbut-2-en-1-one (9): 1H NMR (CDCl3,
500 MHz), d (ppm): 1.95 (s, 3H); 2.14 (s, 3H); 2.33 (s, 3H); 2.45 (s, 3H); 6.43
(s, 1H); 7.03 (s, 1H); 7.03 (d, 1H, J = 7,8 Hz), 7.44 (d, 1H, J = 7.8 Hz). 13C NMR
(CDCl3, 125 MHz), d (ppm): 19.15, 20.58, 20.87, 21.30, 27.75, 124.88, 126.11,
127.68, 128.73, 132.99, 137.49, 140.80, 195.61.
15. Panda, G.; Mishra, J. K.; Shagufta; Dinadayalane, T. C.; Sastry, G. N.; Negi, D. S.;
Indian, J. Chem. Sec. B-Org. Chem. 2006, 45, 276.
16. Hertzler, R. L.; Delphon, J. K.; Eisenbraun, E. J. J. Org. Chem. 1989, 54, 1418.
3,3,4,7-Tetramethyl-1-indanone (10): 1H NMR (CDCl3, 500 MHz), d (ppm): 1.41
(s, 6H); 2.40 (s, 3H); 2.50 (s, 2H); 2.51 (s, 3H); 6.93 (d, 1H, J = 7.5 Hz); 7.12 (d,
1H, J = 7.5 Hz). 13C NMR (CDCl3, 125 MHz), d (ppm): 18.38 (CH3), 19.38 (CH3),