A novel one pot route to flavones under dual catalysis, an organo- and a Lewis acid catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.08.078

Substituted phenylacetylenes react with various o-hydroxy aromatic aldehydes under dual catalysis of piperidine and FeCl₃ in refluxing toluene to yield flavones in good to excellent yield. Atmospheric oxygen acts as stoichiometric oxidant in the process. Some of these compounds had been recently reported to show fair insecticidal activity against Spodoptera frugiperda.

Full text of DOI:10.1016/j.tetlet.2011.08.078

Tetrahedron Letters 52 (2011) 5610–5612
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel one pot route to flavones under dual catalysis, an organo-
and a Lewis acid catalyst
⇑
Gourhari Maiti , Rajiv Karmakar, Rudraksha N. Bhattacharya, Utpal Kayal
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted phenylacetylenes react with various o-hydroxy aromatic aldehydes under dual catalysis of
piperidine and FeCl3 in refluxing toluene to yield flavones in good to excellent yield. Atmospheric oxygen
acts as stoichiometric oxidant in the process. Some of these compounds had been recently reported to
show fair insecticidal activity against Spodoptera frugiperda.
Received 16 June 2011
Revised 12 August 2011
Accepted 13 August 2011
Available online 24 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Flavones
One pot
Dual catalysis
Ferric chloride
Aerial oxidation
Flavones, also known as 2-phenyl-4-chromones represent one
of the largest groups of natural products and are highly diverse.
A large number of derivatives have been identified and the number
is still growing rapidly. The chromone framework is widely identi-
fied as a privileged structure for drug development or pharmaco-
The palladium catalyzed carbonylation of o-iodophenols with
terminal alkynes have become an attractive alternative to synthe-
size chromones, but the scope is limited due to the formation of
five-membered aurones as the side product.12 Yang and Alper have
developed ligand free Pd-catalyzed cyclocarbonylation of
o-iodophenols with terminal alkynes in ionic liquids.7e Considering
therapeutic importance of flavones, one pot diversity oriented
approach is highly desired. We were interested in investigating an
alternative one pot atom-economy route to flavones as delineated
below (Fig. 1).
Herein, we report a new synthetic route to flavones 3 from
2-hydroxyaryl aldehyde 1 and aryl acetylene 2 in the presence of
piperidine (20 mol %) and FeCl3 (10 mol %) under reflux in toluene
in open air (Scheme 1).
It is noteworthy that iron(III) salts/complexes have a rich heri-
tage to catalyze aerial oxidation including photooxidation13 and
have also been used as stoichiometric oxidant in many cases.14
phore. Both natural and synthetic flavones exhibit
a wide
spectrum of biological activity including anti-oxidant, anti-cancer,
anti-HIV, anti-hypertensive, and anti-inflammatory properties.1–5
Because of their antioxidant ability, many of the flavonoids are
responsible for health-promoting functions in organism, which
are important for the prevention of diseases that are associated
with an oxidative damage of membranes, proteins and DNA.6 This
has led to a wide interest among the community of organic chem-
ists to synthesize flavones, both by the development of annulation
methodology7 and by target oriented convergent synthesis.8
Traditionally, chromones have been prepared by the Baker–
Venkatraman rearrangement9 or by annulation involving oxidative
cyclization of various 2-hydroxychalcones and cyclodehydration of
substituted 1-(2-hydroxyaryl)-3-arylpropan-1,3-dione. Later, clas-
sical Baker–Venkatraman reaction have been modified to one pot
synthesis using 2-hydroxyacetophenone derivatives and acyl chlo-
ride in the presence of DBU-pyridine.10 Very recently, Buckle and
co-workers 11 observed that 2-hydroxy acetophenone when heated
with an excess of benzoyl chloride in an open K2CO3 wet acetone
system, flavone was obtained but only in modest yield.
usual
approach
O
O
O
O
O
R
R
Ar
or
+
R
CHO
Ar
Ar
O
H
O
H
O
O
our approach
+
Ar
O
Ar
OH
⇑
Corresponding author.
E-mail address: ghmaiti123@yahoo.co.in (G. Maiti).
Figure 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.078

G. Maiti et al. / Tetrahedron Letters 52 (2011) 5610–5612
5611
Table 2
O
O
One pot synthesis of flavones under dual catalysis
FeCl3(10 mol%)
R1
R2
O
R1
+
O
O
piperidine (20 mol%)
toluene refluxed in
open air, 7-12 h
Ar
O
Ar
FeCl3 (10 mol%)
OH
H
R1
R1
+
3
1
2
piperidine (20 mol%)
toluene, refluxed
in open air
OH
R2
2
1
3
Scheme 1. Synthesis of flavones.
The present investigation involves oxidation by two units of iron
salt. The concept of dual catalysis15 and organocatalysis16 is of
increasing importance in recent times.
Entry
1
Aldehyde
R2
Producta,b
Time (h)
8
Yieldc (%)
CHO
OH
H
3a
80
In a preliminary experiment, a solution of salicylaldehyde 1a
(1.0 mmol) and phenyl acetylene 2a (1.5 mmol) in toluene (3 mL)
was refluxed in the presence of FeCl3 (10 mol %) and piperidine
(20 mol %) for 8 h in open air to afford the desired chromone 3a in
80% yield. Then, to optimize the reaction conditions the same reaction
was studied by using various Lewis acids and organocatalysts, a dual
catalystsystemandalsothecatalyst-solventcombinationunderiden-
tical reaction conditions. The results are summarized in Table 1.
It is quite apparent from Table 1 that among various Lewis acid
catalysts-organocatalysts combination screened, only FeCl3-piperi-
dine catalyst combination afforded the best results with respect to
the reaction time and yield are concerned. It was also found that
the use of 10 mol % of FeCl3 gave the best result. Use of less than
10% of FeCl3 decreases the yieldand more than10 mol % doesnot im-
prove the rate as well as the yield of the product. The presence of aer-
ial oxygen is essential for this transformation without which the
reaction does not occur at all. The role of aerial oxygen in some oxi-
dation reaction is known in the literature.17 It is also very clear from
Table 1 that piperidine is the best choice of the base as a catalyst. It
should be noted here that the primary or tertiary amines could not
catalyze the reaction. This indicates that an imminium ion is formed
with the secondary amine in the reaction pathway.
1a
Cl
CHO
2
H
3b
7
86
OH
1b
1c
3
4
5
1b
1b
1b
4-F
4-Cl
4-Br
3c
3d
3e
8
10
10
87
83
84
Br
CHO
OH
6
7
H
3f
7
82
85
1c
4-Cl
3g
10
CHO
OH
CHO
OH
OMe
8
9
H
3h
3i
12
12
85
84
1d
1d
4-Br
10
H
3j
10
86
1e
1e
11
12
4-Cl
4-Br
3k
3l
8
8
82
86
1e
O2N
CHO
OH
A series of 2-hydroxy arylaldehydes and arylacetylenes were
subjected to the optimized reaction conditions21 and the results
are summarized in Table 2.
13
H
3m
10
74
1f
a
Reaction condition: 2-hydroxy arylaldehyde (1.0 mmol), arylacetylene
Table 1
(1.0 mmol) in 3 mL toluene, FeCl3 (0.1 mmol), piperidine (0.2 mmol), refluxed in
open air.
Optimization of the reaction conditions
O
O
b
All products were characterized by IR, 1H NMR, 13C NMR and HRMS.
O
C
catalyst (10 mol%)
Pure, isolated yield after column chromatography.
Ph
+
amine (20 mol%)
refluxed in open
air, 8 h
Ph
OH
Along with the desired flavones, about 3–5% of o-hydroxy chal-
cone 4 was formed in every cases under the reaction conditions
which could easily be separated by column
1a
2a
3a
Entry
Catalyst
Base
Solvent
Yielda,b (%)
O
1
2
3
4
5
6
7
8
9
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Morphine
N-Methylaniline
Pyrrolidine
K2CO3
Toluene
Xylene
CH3CN
80
72
R1
32
c
R2
DCM
OH
CH3NO2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
C
c
4
37
08
chromatography and characterized by spectral analysis. It is to be
mentioned here that the formation of flavones certainly did not
proceed through chalcone intermediate as o-hydroxy chalcone
when refluxed in toluene in open air with FeCl3 (10 mol %) and
piperidine (20 mol %) could not furnish flavone. Keeping with all
these facts, the probable mechanism for the formation of flavones
is shown in Figure 2.
Various 2-hydroxy arylaldehydes having both positive and
negative inductive and mesomeric groups responded well to the
reaction. In the reaction, atmospheric oxygen was used as the ulti-
mate stoichiometric oxidant leaving only water as the by-product.
2-hydroxy-1-naphthaldehyde did not furnish the desired product,
instead a very complex mixture was formed. 1-Ethynyl-3-nitroben-
zene when used as the terminal alkyne also did not respond to the
63
c
10
11
12
c
Aniline
26
L-Proline
13
14
15
16
17
18
19
20
FeCl3
Nil
p-TsOH
lnCl3
lnCl3
SnCl3
Nil
Toluene
Toluene
Toluene
Toluene
CH3NO2
Toluene
Toluene
Toluene
20
c
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
c
c
c
06
c
Yb(OTf)3
Zncl2
c
a
Reaction condition: salicyaldehyde (1.0 mmol), phenylacetylene (1.0 mmol) in
3 mL of solvent, catalyst (0.1 mmol), amine (0.2 mmol), refluxed in open air for 8 h.
b
Pure, isolated yield after column chromatography.
Desired product not formed.
c

5612
G. Maiti et al. / Tetrahedron Letters 52 (2011) 5610–5612
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FeCl2OH
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Figure 2. Probable mechanism.
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It is very interesting to note that how the variation of catalyst sol-
vent system can lead to different products, the major reactants
remaining similar. Skouta et al.18 showed that the reaction between
salicylaldehyde and phenyl acetylene in the presence of a tributyl-
phosphine and AuCN as the catalyst in toluene at 150 °C afforded iso-
flavone. On the other hand, phenyl acetylene, salicylaldehyde, and
piperidine in the presence of copper(I) halides as catalyst in DMF,
potassium carbonate, and nBu4NBr yielded benzofurans in modest
yield. In the absence of potassium carbonate and nBu4NBr under sim-
ilar reaction condition afforded the propoargyl amine derivatives.19
The compounds 3b and 3f have recently been reported to show
good activity against Spodoptera frugiperda, the fall armyworm
which is regarded as a pest and can wreak havoc with crops if left
to multiply. The 50% lethal times (LT50) of 3b and 3f were shown to
be 53 and 44 h, respectively.20
In conclusion, we have developed a new methodology toward
one pot synthesis of flavones under dual catalysis of piperidine,
an organocatalyst and ferric chloride, a Lewis acid. The notable
advantages of this method are operational simplicity, use of inex-
pensive and eco-friendly FeCl3 as catalyst, employment of atmo-
spheric oxygen as the stoichiometric oxidant and ease of isolation
of products. Further studies in this area to explore the synthetic
applications of the reaction are progress.
21. Representative experimental procedure for the synthesis 2-phenyl-4H-chromen-4-
one (3a): A mixture of 2-hydroxybenzaldehyde (122 mg, 1.0 mmol), phenyl
acetylene (153 mg, 1.5 mmol), anhydrous ferric chloride (16 mg, 0.10 mmol)
and piperidine (17 mg, 0.20 mmol) were added to dry toluene (3 mL) taken in a
25 mL round bottom flask fitted with a reflux condenser and a calcium chloride
guard tube and was refluxed for 6–12 h. Completion of the reaction was
monitored by TLC. The reaction mixture was decomposed with water and
extracted with diethyl ether (3 Â 15 mL), washed with water followed by brine
solution and dried over anhydrous Na2SO4. Filtered and volatiles were removed
in vacuo and the crude residue was purified by column chromatography over
silica gel (100–200 mesh), eluting with 8–15% ethyl acetate in petroleum ether
to afford 3a (178 mg, 80%) as a white solid and 1-(2-hydroxyphenyl)-3-phenyl-
propenone 4a (9 mg, 4%). Spectral and analytical data of 3a: mp 97–98 °C. IR
Acknowledgments
We thank the Department of Chemistry, Jadavpur University for
the financial and infrastructural support from UGC-CAS and
PURSE-DST Programme. R.K. and U.K. thank CSIR, New Delhi for
awarding the fellowships. We are also thankful to Mr. S. Dutta,
IICB, Kolkata for providing instrumental facilities.
(KBr): 1128, 1225, 1375, 1448, 1465, 1495, 1568, 1645, 2355, 2923, 3088 cmÀ1
.
1H NMR (CDCl3, 300 MHz): d 6.84 (s, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.50–7.61 (m,
4H), 7.71 (t, J = 7.5 Hz, 1H), 7.90–7.96 (m, 2H), 8.24 (d, J = 7.5 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): d 107.6, 118.1, 124.0, 125.3, 125.8, 126.4, 129.1, 131.6, 131.8,
133.8, 156.3, 163.5, 178.1. HRMS for [C15H11O2]+ calcd 223.0754; found
223.0748. Spectral and analytical data of 4a: mp 79–80 °C. IR (KBr): 975, 1020,
Supplementary data
1029, 1152, 1235, 1340, 1438, 1448, 1574, 1639 cmÀ1 1H NMR (CDCl3,
.
300 MHz): d 6.95 (t, J = 8.0 Hz, 1H), 7.63–7.67 (m, 3H), 7.89–7.94 (m, 2H), 12.85
(brs, 1H). 13C NMR (CDCl3, 75 MHz): d 118.6, 118.8, 120.0, 120.1, 128.6, 129.0,
129.6, 130.9, 134.6, 136.4, 145.4, 163.6, 193.7.
Supplementary data (1H, 13C NMR spectral data of compound
3b–m) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.08.078.