A Mild and Efficient Route to 3-Vinylchromones in Aqueous Micellar Media

Article abstract of DOI:10.1080/00397911.2015.1084008

A simple, mild, and ecofriendly method has been developed for the synthesis of 3-vinylchromones from 4-oxo-4H-1-benzopyran-3-carboxaldehyde (3-formylchromone) by simple Knoevenagel condensation with various active methylene compounds (AMC) in aqueous mice

Full text of DOI:10.1080/00397911.2015.1084008

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A Mild and Efficient Route to 3-Vinylchromones in
Aqueous Micellar Media
Vikash Kumar, Amrita Chatterjee & Mainak Banerjee
To cite this article: Vikash Kumar, Amrita Chatterjee & Mainak Banerjee (2015): A Mild and
Efficient Route to 3-Vinylchromones in Aqueous Micellar Media, Synthetic Communications,
DOI: 10.1080/00397911.2015.1084008
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Date: 11 September 2015, At: 05:33

A Mild and Efficient Route to 3-Vinylchromones in Aqueous Micellar media
Vikash Kumar1, Amrita Chatterjee1 Mainak Banerjee1
1Department of Chemistry, Birla Institute of Technology and Science, Pilani - K. K.
Birla, Goa Campus, Goa 403 726, India.
Corresponding authors: Dr. Mainak Banerjee, Department of Chemistry, Birla
Institute of Technology and Science,Pilani - K. K. Birla, Goa Camps, Goa- 403 726,
India. Email: mainak@goa.bits-pilani.ac.in
Corresponding authors: Dr. Amrita Chatterjee, Department of Chemistry, Birla
Institute of Technology and Science,Pilani - K. K. Birla, Goa Camps, Goa -403 726,
India. Email: amrita@goa.bits-pilani.ac.in
Abstract
A simple, mild and eco-friendly method has been developed for the synthesis of 3-
vinylchromones from 4-oxo-4H-1-benzopyran-3-carboxaldehyde (3-formylchromone) by
simple Knoevenagel condensation with various active methylene compounds (AMC) in
aqueous micellar media in the presence of catalytic amounts of CTAB and DABCO. In
case of malonic acid as AMC, the reaction resulted formation of only Doebner
decarboxylated products under the standard reaction condition. It has been also observed
that 3-formylchromone derivatives primarily undergo tandem Knoevenagel and Michael
reactions in the presence of >2 equiv. of ethyl acetoacetate to produce benzophenone
derivatives, by opening of pyran ring, as the sole product in high yields.
1

Key words: micellar media, surfactants, Knoevenagel condensation, Doebner
decarboxylation, active methylene compounds, 3-vinylchromones.
INTRODUCTION
Chromone is the structural scaffold of a variety of bioactive compounds of synthetic as
well as of natural origin with great pharmaceutical importance.[1, 2] From a synthetic
viewpoint, 3-formylchromone remains as the key starting material for many of these
important heterocyclic systems because of the availability of three electron deficient
sites: the C-2 carbon, the aldehyde carbon and the C-4 carbon of the carbonyl group
(Figure 1A). Therefore, 3-formylchromone is able to serve as a heterodiene as well as a
dienophile or a Michael acceptor based on the available substrates and reaction condition
leading to the construction of a great variety of heterocyclic systems.[3] At the same time,
chemical modification of this scaffold is a delicate issue as valuable pharmacophores
derived from this moiety are vulnerable to a number of nucleophiles, organic bases or
strong acids due to its high reactivity.[4] Therefore, development of mild conditions for
2

further functionalization of C-3 position of 3-formylchromone and pharmacological
utilization draws significant research interests till date.[5] In particular, Knoevenagel
condensation reactions of 3-formylchromones with compounds having active methylene
group leading to formation of 3-vinylchromones were well studied.[6] Such types of
condensations are mostly achieved by conventional methods in organic medium in the
presence of acids or bases. However, present environmental concerns demand greener
alternatives to construct these important heterocycles. So far, there are only limited
numbers of green approaches for vinylation of 3-formylchromones by Knoevenagel
condensation [7] including a catalyst free process in water at elevated temperature.[7b]
Therefore, the development of a new and efficient “green” protocol for this purpose is
worthy pursuit.
In the context of “green chemistry and its 12 principles” water as solvent has gained
immense popularity due to being inexpensive, non-toxic, non-flammable, widely
abundant in nature and environmentally benign. The main problem of insolubility of most
of the organic compounds in water is commonly solved by the use of surface-active
compounds.[8] They form a micellar, colloidal, or other organized phase hydrophobic
interior of which acts as a confined nanoreactor and bring the organic reagents in close
proximity to allow the reaction to occur.[9] In particular, dehydration reactions, which
often require anhydrous conditions and therefore, one of the most challenging tasks to
accomplish in water, have been successfully carried out by our group[10] and others[11] in
aqueous media in the presence of catalytic amounts of surfactants. Knoevenagel
condensation is eventually a dehydration reaction and there are several reports of carrying
3

out this reaction in water catalyzed by a surfactant.[12] However, to the best of our
knowledge, Knoevenagel condensation of 3-formylchromone leading to 3-
vinylchromones was not explored in a micellar medium.
RESULTS AND DISCUSSION
We report herein, CTAB catalyzed efficient synthesis of 3-vinylchromones by simple
Knoevenagel condensation of 3-formylchromones with various active methylene
compounds in aqueous media in the presence of DABCO as co-catalyst (Scheme 1). The
main role of CTAB is to form micelles in aqueous media that act as nanoreactors to carry
out organic reactions. Although most of the active methylene compounds are moderately
to freely soluble in water, 3-formylchromones have very limited aqueous solubility.
Therefore, condensation reaction could proceed in an aqueous medium only at higher
temperature.[7b] We anticipated, a micellar medium will be helpful to carry out such
reactions more efficiently at a much milder condition because both the reactants would
preferably stay in close proximity inside the hydrophobic interior of the micelles allowing
the reaction to proceed spontaneously. Indeed, the methodology worked out well for
various 3-formylchromones and compounds containing active methylene group.
Interestingly, 3-formylchromones in condensation with ethyl acetoacetate mainly produce
benzophenone derivatives by opening of pyran ring via tandem Knoevenagel and
Michael reactions (Scheme 1).
We started our investigation with a focus on standardizing the reaction conditions. First,
the formation of the emulsion droplets were examined by taking optical micrograph of
4

different surfactant containing aqueous solutions of reaction mixtures after 5 min of
stirring at room temperature (Figure 2A). Dynamic light scattering (DLS) experiments of
those solutions confirmed that the size of emulsion droplets is in the nanometer range
(225-420 nm) (Figure 2B). Then the suitable condition for the Knoevenagel condensation
was established by thorough screening of various surfactants, organic bases and reaction
temperature. We selected four different class of surfactants viz. SDS (anionic), DBSA
(Brønsted acid), CTAB (cationic), and Triton X-100 (neutral) and conducted a model
reaction between equimolar mixture of 3-formylchromone (1a) and diethylmalonate (2a)
to find out the most suited surfactant for this reaction. It was found that three surfactants
(SDS, CTAB, and Triton X-100) out of four could initiate the formation of the desired
product (3a) but the reaction was very sluggish at room temperature (Table 1, entry 1-3).
Even gentle warming of the reaction mixture was not very effective in terms of the rate of
formation of 3a (Table 1, entry 5-7). On the other hand, DBSA failed to initiate the
reaction even after 12 h (Table 1, entry 4, 8). However, addition of 10 mol% of a suitable
amine (such as DABCO) as co-catalyst boosted the rate of product formation by several
fold (Table 1, entry 9-13). Furthermore, significant enhancement in rate was observed
when the same reaction was carried out at 40 °C (Table 1, entry 10) instead of room
temperature (Table 1, entry 9). In these cases, the model reaction was carried out using 10
mol% of CTAB as the surfactant. Among several different amines DABCO was found to
be most suitable in terms of yield and time required for completion of the reaction.
Presumably, DABCO, being more hydrophobic in nature, prefers to stay inside the
hydrophobic interior of micelles as compared to other bases used for this purpose and
therefore, it could act as a better catalyst for this reaction. Once DABCO was identified
5

as most suitable co-catalyst, the same model reaction was carried out with different
surfactants and it was found that all the surfactants (10 mol%) could catalyze the
condensation reaction in the presence of 10 mol% of DABCO at 40 °C to afford the
desired product (3a) in moderate to good yields (Table 1, entry 10, 14-16). Both DBSA
and SDS were found less efficient as catalyst for this reaction, whereas, yields of the final
product were high for both CTAB and Triton X-100. As expected, catalytic ability of
DBSA-DABCO combination is poor as DBSA reduces the catalytic activity of DABCO
by protonation (Table 1, entry 15). Among the rest, CTAB catalyzes the reaction better,
presumably due to stronger binding of the CTAB with the substrates, which is expected
as CTAB has higher hydrocarbon content in its core region than others.[13] As a part of
our study, we also varied mol% of both CTAB and DABCO, and changed temperature to
arrive at the ideal reaction condition. As mentioned in table 1, decrease in concentration
of CTAB (Table 1, entry 20) or DABCO (Table 1, entry 17) in the reaction mixture slows
down the reaction, whereas, use of excess CTAB (Table 1, entry 21) and DABCO (Table
1, entry 18, 19) hardly shows any effect on the reaction rate or the yield of final product
(3a). At the same time, the reaction temperature above 40 °C did not make a significant
difference in the reaction rate and the yield (Table 1, entry 22, 23). Therefore, use of 10
mol% of CTAB as catalyst and 10 mol% of DABCO as co-catalyst and gentle heating (at
40 °C) was considered as optimum condition for further studies.
To test the generality of this method, various 3-formylchromones were treated with
different compounds containing active methylene group in the presence of CTAB
(10 mol%) and DABCO (10 mol%) at the optimized reaction condition. All the
6

substrates were found to undergo smooth reaction to afford 3-vinylchromones in
high yields within few hours (Table 2). Each of the 3-vinylchromones was
thoroughly characterized by 1H NMR, 13C NMR, ESI-MS, IR and CHN analysis,
and compared with the reported data. It was found that a substitution at the
aromatic ring of 3-formylchromones does not have much influence in the final
yield of the products. This is presumably because of the fact that the substituent is
located far away from the reaction center. However, presence of electron
withdrawing group does influence a little on the reactivity of the corresponding 3-
formylchromone derivatives. Thus, the reactions involving 3-formyl-6-nitro-
chromone (1d) completed in shorter time (Table 2, entry 18, 19, 20) than similar
reactions with unsubstituted 3-formylchromones (Table 2, entry 1, 5, 6). Among
active methylene compounds malononitrile (2d) reacted much faster than the
others to produce the desired condensation products in high yields (Table 2, entry
4, 10). Interestingly, however, condensation of 3-formylchromones with malonic
acid (2f) afforded Doebner decarboxylated products (3f, 3l, 3q and 3t; Table 2,
entry 6, 12, 17 and 20, respectively) as the only isolated product as revealed by
spectral studies and CHN analysis. The coupling constant (J = 15.6 Hz) of H-
atoms across the olefinic double bond revealed that they bear trans geometry.[6d]
As reported by Nohara et al.,[2d] these chromone derivatives bearing an acrylic acid
residue at C-3 display antiallergic activity. These compounds were previously
achieved only by refluxing the reaction mixture in pyridine. We observed that the
micellar medium is suitable to spontaneously carry out an in situ decarboxylation
to afford these products in high yields. Moreover, the yields of these bioactive
7

compounds using this method were much higher than the previously reported
procedure.[2d, 6d] Although the yields were highly satisfactory for all the other
entries, the reaction between ethyl acetoacetate (EAA) and 3-formylchromone did
not afford the condensation product, 3b in high yield (Table 2, entry 2). It was
observed that the major product of the reaction between equimolar mixture of 1a
and 2b was a benzophenone derivative (4a). The formation of the benzophenone
derivative, 4a by opening of pyran ring by Knoevenagel condensation followed by
Michael reaction was previously reported by W. D. Jones et al. in ethanolic
medium in the presence of one equiv of organic base in poor yield.[14]
Encouraged by the fact that 3-formylchromone mainly undergoes tandem Knoevenagel
and Michael reaction in the presence of EAA to produce benzophenone derivative, 4a
several reactions were carried out between various 3-formylchromones (1 equiv) and
excess EAA (2.2 equiv) to ensure formation of benzophenone derivatives (4) as the main
product (Table 3). As expected, the reactions produced the benzophenone derivatives (4)
in high yields. None of the simple Knoevenagel condensation product (3) was observed
in the final reaction mixture. Presumably, the benzophenone derivatives are formed by
stepwise attack of two molecules of EAA to 3-formylchromones (Figure 3). At first,
EAA undergoes Knoevenagel condensation to form expected 3-vinylchromones (3).
Next, another molecule of EAA goes for Michael addition followed by opening of the
chromone ring and cyclization to afford the benzophenone derivatives, 4. Once again, it
was found that the nature of the substitutions in the aryl ring of chromone moiety does
not have great influence on the reactivity and the yield of the final product. All the
8

reactions were completed within 2 h and the yields were in the range 82-90%. Although
variation was made only in the chromone moiety, it is expected that a variety of
acylacetate esters (RCOCH2COOR’) would also undergo similar reactions to produce a
benzophenone derivative.
CONCLUSION
A facile and ‘green’ method has been developed for the synthesis of 3-vinylchromones
from 3-formylchromones using different active methylene compounds in organized
aqueous media in the presence of CTAB as surfactant and DABCO as mild basic catalyst.
A broad range of vinyl derivatives from various 3-formylchromones were obtained using
this method. In case of malonic acid, Doebner decarboxylated products and in case of
excess ethyl acetoacetate, benzophenone derivatives were obtained as major products.
Overall, this method is environmentally benign, cheap, safe, high yielding, and a much
improved method than other available methods for the synthesis of 3-vinylchromones
from 3-formylchromones.
EXPERIMENTAL SECTION
A Representative Procedure For The Synthesis Of 3-Vinylchromones (3): Synthesis
Of 3-[(6-Methyl-4-Oxo-4H-1-Benzopyran-3-Yl)-Methylene]-Pentan-2,4-Dione (3k).
To a solution of CTAB (18.2 mg, 0.05 mmol) in H2O (2 mL) were added 6-methyl-3-
formylchromone (94.0 mg, 0.5 mmol), DABCO (5.6 mg, 0.05 mmol), and acetyl acetone
(51.3 µL, 0.5 mmol) successively at room temperature in a 10 mL round-bottom flask.
The reaction mixture was sonicated for 2 min and then stirred at 40 °C for 40 min. The
9

reaction was monitored by TLC. The crude product was extracted with ethyl acetate,
washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The crude
product was purified by column chromatography (silica gel, 60-120 mesh) using a
mixture of ethyl acetate and hexane (1:5) as the eluent.
Light yellow solid, mp. 138-139 °C; 1H NMR (400 MHz, CDCl3) δ (ppm): 2.34 (s, 3H),
2.45 (s, 3H), 2.46 (s, 3H), 7.36 (d, J = 8.5 Hz, 1H), 7.49-7.52 (m, 2H), 8.0 (s, 1H), 8.26
(s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 21.1, 26.4, 31.4, 118.1, 118.6, 123.3,
125.6, 130.9, 135.8, 136.4, 144.3, 154.3, 156.8, 175.6, 197.4, 204.2; IR (KBr): 3066,
1702, 1650 cm-1; MS (ESI): m/z 271 (M + H)+. Anal. Calcd. for C16H14O4: C, 71.10; H,
5.22. Found: C, 71.24; H, 5.27.
A Representative Procedure For The Synthesis Of Benzophenone Derivatives (4):
Synthesis Of Diethl-5-(2-Hydroxy-5-Methylbenzoyl)-2-Methyl-1,3-
Benzenedicarboxylate (4b).
To a solution of CTAB (18.2 mg, 0.05 mmol) in H2O (2 mL) were added 6-methyl-3-
formylchromone (94.0 mg, 0.5 mmol), DABCO (5.6 mg, 0.05 mmol), and ethyl
acetoacetate (140 µL, 1.1 mmol) successively at room temperature in a 10 mL round-
bottom flask. The reaction mixture was sonicated for 2 min and then stirred at 40 °C for 2
h. The crude product was extracted with ethyl acetate, washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuum. The crude product was purified by
column chromatography (silica gel, 60-120 mesh) using 8% ethyl acetate in hexane as the
eluent.
10

Light yellow solid, mp. 75-77 °C; 1H NMR (400 MHz, CDCl3) δ (ppm): 1.42 (t, J = 8.0
Hz, 6H), 2.29 (s, 3H), 2.82 (s, 3H), 4.42 (q, J = 8.0 Hz, 4H), 7.02 (d, J = 8 Hz, 1H), 7.33
(d, J = 2.5 Hz, 1H), 7.38 (dd, J1 = 2.5 Hz, J2 = 8.0 Hz, 1H), 8.19 (s, 2H), 11.68 (s, 1H,
exchangeable); 13C NMR (100 MHz, CDCl3) δ (ppm): 14.2, 18.2, 20.5, 61.7, 118.4,
128.2, 132.8, 132.9, 133.3, 135.2, 137.9, 143.3, 161.2, 167.0, 199.3; IR (KBr): 2983,
1725, 1639 cm-1; MS (ESI): m/z 371 (M + H)+. Anal. Calcd. for C21H22O6: C, 68.10; H,
5.99. Found: C, 67.89; H, 6.00.
SUPPORTING INFORMATION
Full characterization data of all compounds and selected 1H & 13C NMR spectra for this
article can be accessed on the publisher’s website. Please make the words “publisher’s
website” a live DOI link.
ACKNOWLEDGEMENTS
M.B. thanks CSIR (India) (Project No. (02)0075/12/EMR-II) for financial support. V.K.
is indebted to CSIR (India) for SRFship.
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Table 1. Effect of surfactant, temperature and base:
Entry Surfactant
mol % of Base
surfactant
mol
Time
T (°C) Yield of
% of (h)
base
3a (%)
1
SDS
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
-
-
12
12
12
12
12
12
12
12
4
rt
10a
16a
12a
nd
2
CTAB
-
-
rt
3
Triton X-100
DBSA
-
-
rt
4
-
-
rt
5
SDS
-
-
40
40
40
40
rt
24a
36a
28a
nd
6
CTAB
-
-
7
Triton X-100
DBSA
-
-
8
-
-
9
CTAB
DABCO
DABCO
10
10
56a
78
10
11
12
13
14
15
16
CTAB
1
40
40
40
40
40
40
40
CTAB
Piperidine 10
Pyrrole 10
L-Proline 10
2.5
4
76
CTAB
80
CTAB
6
72
SDS
DABCO
DABCO
DABCO
10
10
10
2
60
DBSA
4
42a
71
Triton X-100
2
15

17
18
19
20
21
22
23
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
10
10
10
5
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
05
20
100
10
10
10
10
2.5
1
40
40
40
40
40
50
60
68
75
82
48a
82
76
80
0.75
3
20
10
10
1
1
1
aIncomplete conversion, starting material left out; nd: not determined
16

Table 2. Condensation of 3-formylchromones with active methylene compounds (AMC):
Entr
y
R
X
Y
AM Product
C
Tim
e
%
Ref
.
Yiel
(min d
)
1
2
3
H
H
H
-
-
60
60
15
78
15
14
7c
2a
2b
2c
CO2C2
CO2C2
H5
-
H5
-
22a
COCH3 CO2C2
H5
-CN
-
79
CO2C2
H5
4
5
6
H
H
H
-CN
-
-CN
10
81
83
88
7c
14
6d
2d
2e
2f
-
30
COCH3 COCH3
-COOH -COOH
150
17

7
8
H
-CN
-
-
20
75
85
82
7c
15
2g
2a
CONH2
6-
-
Methy CO2C2
CO2C2
H5
l
H5
9
6-
-CN
-
15
10
40
180
30
40
96
83
79
83
85
92
7c
7c
--
2c
2d
2e
2f
Methy
CO2C2
H5
l
10
11
12
13
14
6-
-CN
-CN
Methy
l
6-
-
-
Methy COCH3 COCH3
l
6-
-COOH -COOH
6d
7c
--
Methy
l
6-
-CN
-
2g
2a
Methy
CONH2
l
6-
-
-
Brom CO2C2
H5
CO2C2
H5
o
18

15
16
17
18
6-
-CN
-
15
99
84
98
90
90
--
2c
2e
2f
Brom
o
CO2C2
H5
-
6-
-
30
--
Brom COCH3 COCH3
o
6-
-COOH -COOH
120
40
6d
--
Brom
o
6-
-
-
2a
Nitro CO2C2
H5
CO2C2
H5
-
19
20
6-
-
15
60
--
2e
2f
Nitro COCH3 COCH3
6-
-COOH -COOH
93
2d
Nitro
aThe reaction produced benzophenone derivative, 4a in 32% yield.
19

Table (3) Condensation of 3-formylchromones with ethyl acetoacetate:
Entry
R
Product
Time (h)
%Yield
Ref.
1
H
1.5
82
14
2
6-Methyl
2.0
88
--
3
4
6-Bromo
6-Nitro
1.5
1.0
83
90
--
--
20

Figure 1. A) 3-Formylchromone and its various reactive centers, B) some
pharmacologically active 3-vinylchromone derivatives.
21

Scheme 1. Condensation of 3-formylchromones using various active methylene
compounds (AMCs) in micellar media.
22

Figure 2. A) A typical optical micrograph of vesicles formed in an aqueous solution of
different 3-formylchromones and active methylene compounds in the presence of CTAB,
B) DLS data of CTAB showing formation of aggregates.
23

Figure 3. Mechanitic pathway of the formation of benzophenone derivative (4a) in
micellar media.
24