Synthesis of 3-substituted carboxylate/carboxamide flavone derivatives from 4-hydroxycoumarin, β-nitrostyrene and alcohol/amine using multicomponent reaction

Article abstract of DOI:10.1016/j.tetlet.2016.03.026

A wide range of 3-substituted carboxylate/carboxamide flavone derivatives were synthesized from 4-hydroxycoumarin, β-nitrostyrene and alcohol/amine using multicomponent reaction in the presence of N,N-dimethyl-4-aminopyridine (DMAP). Good yield, short rea

Full text of DOI:10.1016/j.tetlet.2016.03.026

Accepted Manuscript
Synthesis of 3-substituted carboxylate/carboxamide flavone derivatives from 4-
hydroxycoumarin, β-nitrostyrene and alcohol/ amine using multicomponent
reaction
Suchandra Bhattacharjee, Abu T. Khan
PII:
S0040-4039(16)30249-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.026
TETL 47414
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
15 February 2016
8 March 2016
Please cite this article as: Bhattacharjee, S., Khan, A.T., Synthesis of 3-substituted carboxylate/carboxamide flavone
derivatives from 4-hydroxycoumarin, β-nitrostyrene and alcohol/ amine using multicomponent reaction,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.026
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Graphical Abstract
Synthesis of 3-substituted
Leave this area blank for abstract info.
carboxylate/carboxamide flavone derivatives
from 4-hydroxycoumarin, β-nitrostyrene and
alcohol/ amine using multicomponent
reaction
Suchandra Bhattacharjeea and Abu T. Khana,b*

1
Tetrahedron Letters
Synthesis of 3-substituted carboxylate/carboxamide flavone derivatives from 4-
hydroxycoumarin, β-nitrostyrene and alcohol/ amine using multicomponent reaction
Suchandra Bhattacharjeea and Abu T. Khana,b
a Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
b Vice-Chancellor, Aliah University, IIA/27, New Town, Kolkata-700 156, West Bengal, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A wide range of 3-substituted carboxylate/carboxamide flavone derivatives were synthesized
from 4-hydroxycoumarin, β-nitrostyrene and alcohol/amine using multicomponent reaction in
presence of N,N-dimethyl-4-aminopyridine (DMAP). Good yield, short reaction time, atom
economy, cost effective and use of non-toxic organo-catalyst are some of the remarkable
advantages of the present protocol.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions (MCR)
4-hydroxycoumarin
β-nitrostyrene
alcohol/ amine
N, N-dimethyl-4-aminopyridine (DMAP)
3-substituted flavone
The most prevailing strategy for the synthesis of highly
functionalized heterocyclic scaffolds is Multicomponent reaction
(MCR).1 It integrates three or more building blocks in an
economic and ecofriendly manner to get the desired product in a
single step. As a matter of fact, it has gained a significant
position in organic synthesis.2 The design of novel MCRs, based
upon the synthesis of oxygen comprising heterocycles,3
especially flavone4 moieties are suitable synthetic targets for
modern researchers. Flavones, a class of flavonoids also known
as 2-aryl-4H-chromene-4-one, are widely distributed in nature,
mainly found in cereals and herbs, and have an imperative aspect
in pharmaceutical industries.5 Figure 1 shows some of the
naturally occurring pharmacologically active flavone scaffold.
catalytic conditions,6 olefination of aldehydes with
hydroxyphenylpropiolates,7 acylation of anionic flavone,8 solvent
mediated reactions of 4-hydroxycoumarin with β-nitrostyrene,
9
cyclization of carbonates facilitated by the catalytic amount of
PBu3.10 Though all the above mentioned protocols for the
synthesis of substituted flavones are quite useful, but there are
limitations like longer reaction time,9 low yields,9 uses of
expensive catalyst,7,10 and loading of excess catalyst.9 The
synthetic protocols were found unproductive for the synthesis of
3-carboxamide-flavone derivatives.9,10 Consequently to develop
an efficient synthetic route to overcome the shortcomings of the
reported protocols are a valid exercise for the researcher.
N,N-dimethyl-4-aminopyridine (DMAP) is
a Lewis base,
extensively employed as a nucleophilic-catalyst for various
organic reactions such as trans esterification,11 acylation,12
Michael’s addition13 and Baylise-Hillman reactions.14 The
catalyst has also been used for different multicomponent
reactions for the synthesis of heterocycles by us15 as well as by
other research groups.16
Figure 1: Some naturally occurring compounds containing
flavone skeleton
A detailed analysis of the reported literature discloses that
many strategies were developed for the synthesis of flavone
moieties, but very few methods have known for the synthesis of
3-substituted carboxylate/carboxamide flavone derivatives.
Classical methods were acylation of ester in presence of different
———
Scheme 1: One-pot three-component synthesis of 3-substituted
flavone derivatives
 Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2582349; e-mail: atk@iitg.ernet.in

2
Tetrahedron Letters
In continuation of our constant efforts in exploring DMAP for
(E)-(2-nitrovinyl) benzene in ethanol under similar conditions,
the desired product 4ab was obtained in 85% yield (Table 2,
entry 2). The scope and efficacy of the synthetic routes were
explored by reacting 4-hydroxycoumarin with β-nitrostyrene
having key functional groups such as halides, nitro, methyl,
methoxy, etc. under optimized reaction conditions and the
desired products were obtained in good yields. It was noted that,
β-nitrostyrene having electron-donating group reacted faster and
gave the better yield than β-nitrostyrene with electron-
withdrawing groups (Table 2, entries 1, 3-7). Next, the protocol
was examined by treating 4- hydroxycoumarin, 4- methyl
nitrostyrene with various alcohols. Using alcohol with bigger
aliphatic groups, the yields of the desired compounds were found
to decrease. Reaction in methanol proceeds smoother and faster,
and was able to produce the best yield (Table 2, entry 13) then
any other alcohols in the series (Table 2, entries 8-13). The
reaction with 4-penten-1-ol was slowest and produces the least
yield (Table 2, entry 12). The protocol was found ineffective in
cases of sterically hindered alcohols like t-butanol, 3-phenyl-1-
propanol (Table 2, entries 14-15) as well as phenol (Table 2,
entry 16).
the construction of biologically active heterocycles, we hereby
report a highly efficient one-pot three component reaction for the
synthesis of 3-substituted-flavone derivatives from 4-
hydroxycoumarin, β-nitro styrene and alcohol/ amine as shown in
Scheme 1.
To find the optimal conditions for the synthesis of 3-substituted
flavone derivatives, various reactions were tried out with 4-
hydroxycoumarin (1 mmol), 4-chloro phenyl nitrostyrene (1
mmol) and ethanol (4 mmol). Initially, reaction has been carried
out with 0.2 mmol of DMAP (Table 1; entry 1) furnished only
17% of the required product after 24 h of refluxing. The product
was purified by chromatographic separation and found to be 3-
1
substituted flavone 4aa, as confirmed by IR, H NMR and mass
spectra. In H NMR spectra of product 4aa, quartet at δ 4.25 for
1
2H and triplet at δ 1.19 for 3H clearly indicate the presence of an
ethoxy group into the molecule. Repeating the above experiment
with 0.4 mmol, 0.6 mmol and 1 mmol of DMAP, the yield of the
product was substantially increased from 30% to 80%
accompanied by decrease of duration of the reaction from 24 h to
5 h. (Table 1; entries 2-4). Performing similar experiment with
1.5 mmol of DMAP, resulted in insignificant change in yield and
time (Table 1; entry 5). The identical reaction was found
unproductive at room temperature with no product formation
(Table 1; entry 6). The same set of reactions was carried out with
other basic catalysts like piperidine, DBU, DABCO and NaOH
and was proved ineffective (Table 1; entries 7-10). No product
was formed in the absence of catalyst (Table 1; entry 11). From
these experimental outcomes, it was clear that catalyst played an
important role in formation of the product 4aa, and 1 mmol of
DMAP was adequate enough to carry out the reaction in terms of
efficacy of time and yield.
Table 2: Substrate scope and yields of 3-carboxylate flavone
derivatives (4a)a
Table 1: Optimized condition for the synthesis of 3-substituted
flavone derivatives
Entry
R1
R2OH
Time
(h)
Yieldb
(%)
Product
1
2
3
4
5
6
4-Cl
H
Et OH
Et OH
Et OH
Et OH
Et OH
Et OH
5
4.5
5
80
85
79
86
88
87
4aa
4ab
4ac
4ad
4ae
4af
4-Br
4-Me
4-OMe
2
Entry
Catalyst
Mol%
Temp
Time (h)
Yieldb %
2.5
3
3-OMe-4-
OMe-5-
OMe
1
2
3
4
5
6
7
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
Piperidine
0.2
0.4
0.6
1
70C
70C
70C
70C
70C
RT
24
24
18
5
17
30
50
80
81
00
00
7
8
9
2- NO2
4-Me
Et-OH
5.5
6
79
77
72
4ag
4ah
4ai
allyl-OH
4-Me
furfuryl-
OH
crotyl-OH
8
10
11
4-Me
4-Me
7
4
76
78
4aj
1.5
1
4.5
24
24
Propargyl-
OH
4-pentene-
OH
4ak
12
4-Me
9
70
4al
1
70C
13
14
15
4-Me
4-Me
4-Me
Me-OH
2
90
4am
8
DBU
DABCO
NaOH
None
1
1
70C
70C
70C
70C
24
24
24
24
00
00
00
00
t-butanol
12
12
N.R
N.R
-
-
-
9
3-phenyl-1-
propanol
10
11
1
4-Me
Phenol
24
N.R
16
00
aThe reactions were carried out with 4-hydroxycoumarin (1 mmol) β-
nitrostyrene (1 mmol), and alcohol (4 mmol) in the presence of different
catalyst at reflux. bIsolated yields.
aThe reactions were carried out with 4-hydroxycoumarin (1 mmol), 4-chloro
phenyl nitrostyrene (1 mmol), and ethanol (4 mmol) in the presence of
different catalyst at reflux. bIsolated yields.
To establish the optimal reaction conditions, we initially
investigated a reaction with a mixture of 4-hydroxycoumarin,

3
On the lookout for further scope of the reaction, we investigated
the nucleophilicity of the reaction by amine as shown in table 3.
Various amine moieties like aliphatic, benzylic, cyclic amines
were considered by conducting the reaction with 4-
hydroxycoumarin and 4-methyl nitrostyrene, the desired products
4ba-4bd were obtained in moderate yield. Unfortunately,
reactions failed to give the desired product in case of aromatic
amine like aniline and secondary amine, for example, diisopropyl
amine (Table 3, entry 5 and 6) respectively.
intermediate C, undergoes an intramolecular cyclization by
releasing nitro methane to form D, which undergoes an oxidation
resulting in the final product 4 (Scheme 2).
Table 3: Substrate scope and yields of 3-carbamide flavone
derivatives (4b)a
Entry
R1
R2NH2
Butyl
Time
(h)
Yieldb
(%)
Product
1
2
3
4
4-Me
4-Me
4-Me
4-Me
12
8
65
69
68
66
4ba
4bb
4bc
4bd
amine
(s)-Phenyl
ethyl amine
Cyclohexyl
amine
Scheme 2. Plausible mechanism for the formation of 3-
substituted flavone derivatives 4
15
6
Benzyl
amine
5
6
4-Me
4-Me
Aniline
24
24
N.R
N.R
-
-
In summary, we have demonstrated a new synthetic protocol for
the synthesis of 3-substituted flavone derivatives by using one
pot three component reaction of 4-hydroxycoumarin, β-nitro
styrene and alcohol/amine by utilizing an organo-catalyst DMAP.
The present protocol is enhanced in terms of yield, reaction time
and conditions as compared to the previous methods. Moreover,
the protocol was successful for the synthesis of 3-carboxamide–
flavone derivatives, which was not reported earlier.
Diisopropyl
amine
aThe reactions were carried out with 4-hydroxycoumarin (1 mmol) β- nitro
styrene (1 mmol), and ammine (4 mmol) in the presence of different catalyst
at reflux. bIsolated yields
All the synthesized compounds were fully characterized by IR,
NMR and Mass Spectra. In IR spectrum, compound 4aa-4am
and 4ba-4bd showed two characteristic strong absorptions at the
range of 1718-1732 cm-1 and 1590-1645 cm-1 due to the carbonyl
group present in the molecule. The mass spectra of all the
compounds exhibited molecular ion peaks at the appropriate m/z
values. For further confirmation, the structure of the compound
4ad was determined by single-crystal X-ray crystallography
(Figure 2).
Acknowledgments
S.B. is thankful to IIT Guwahati for her research fellowship.
A.T.K is thankful to CSIR, New Delhi for research grant no.:
02(0181)/14/EMR-II for financial support. The authors are
grateful to the Department of Science and Technology, New
Delhi for financial assistance for creating single XRD facility in
the Department of Chemistry under FIST programme. The
authors also acknowledge to the Director, IIT Guwahati for
providing laboratory facility.
Supplementary Material
Supplementary data (X-ray crystallographic data (CIF files) of
1
4ad, spectral data of all compounds and copies of H and 13C
NMR spectra of products) associated with this article can be
found, in the online version, at
References and notes
1.
(a) Orru, R. V. A.; Ruijter, E. Synthesis of Heterocycles via
Multicomponent Reactions I & II, 1st Ed.; Springer: Heidelberg,
Germany, 2010. (b) Dömling, A. Chem. Rev. 2006, 106, 17..
(a) González, C. J.; Constable, D. J. C. Green Chemistry and
Engineering, John Wiley & Sons, Inc.: New Jersey, 2011
(a) Malakar, C. C.; Schmidt, D.; Conrad, J.; Beifuss, U. Org.Lett.
2011, 13, 1972. b) Ye, L.W.; Sun, X. L.; Zhu, C. Y.; Tang, Y.
Org. Lett. 2006, 8, 3853. c) Bhattacharjee, S.; Das, D. K.; Khan,
A. T. Synthesis 2014, 73. d) Khan, A. T.; Choudhury, A.; Ali, S.;
Khan, M. M. Tetrahedron Lett.2012, 53, 4852.
Figure 2. X-ray crystal structure of 3-carboxylate flavone
derivative 4ad
2.
3.
Although the mechanism of the reaction was not established
experimentally, the product 4 can be believed formed by using
the following mechanistic pathway: First 4-hydroxycoumarin
undergoes Michael-addition reaction with nitro-olefin in presence
of DMAP, resulting in an adduct A. DMAP being a strong
nucleophile, attacks at the carbonyl center of A leading to the
formation of the reactive amide center in B. The intermediate B
cannot form any side products but immediately reacts with an
alcohol or amine forming an intermediate C. Eventually
4.
(a) Verma, A. K.; Pratap, R. Tetrahedron. 2012, 68, 8523. b)
Singh, M. ; Kaur, M.; Silakariet, O; Eur. J. Med. Chem. 2014,
84, 206.

4
Tetrahedron Letters
5.
a) Du, Z.;Ng, H.; Zhang, K.;Zeng, H.; Wang, J.; Org. Biomol.
disappearing of starting material and formation of new spot) was
observed by TLC of Ethyl acetate and hexane (15: 85%). After
the formation of the product, the crude reaction mixture was
extracted with EtOAc (2 × 10 mL), the combined organic layers
were washed with H2O (10 mL), and dried (Na2SO4). The solvent
was removed in vacuo and the residue was chromatographed on
silica gel (60–120 mesh) to afford the pure products in 65-90%
yields (Table 2 and 3).
Chem. 2011, 9, 6930. (b) Sun, Y.; Liu, G.; Huang, H.; Yu, P.
Phytochemistry. 2012, 75, 169.
a) Coppola, G. M.; Dodsworth, R.W.; synthesis, 1981. 523. b)
Shcherbakov, K.V.; Burgart, Y.V.; Saloutin, V.L.; Russ. J. Org.
Chem, 2013, 49, 719. c) Hormi, O. E. O.; Moisio, M. R.; Sund,
B. C. J. Org. Chem. 1987, 52, 5272.
6.
7.
8.
9.
Wang, N.; Cai, S.; Zhou, C.; Lu, P.; Wang, Y. Tetrahedron.
2013, 69, 647
Ethyl 2-(4-chlorophenyl)-4-oxo-4H-chromene-3-carboxylate
(4aa):
Costa, A.M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.; Varma, R.
S. J. Chem. Soc., Perkin Trans. 1; 1985, 799
Zanwar, M. R.;Raihan, M. J.; Gawande, S. D.;Kavala, V.;
Janreddy, D.; Kuo, C-W.;Ambre, R.; Yao, C-F. J. Org. Chem.
2012, 77, 6495.
Orange semi solid (0.262g, 80%),
IR (KBr): 1731, 1645, 1575, 1466, 1381, 1090, 1015, 761cm-1.
1H NMR (400 MHz, CDCl3): 8.22 (d, J = 8.0 Hz, 1H), 7.69 (d, J
= 6.8 Hz, 3H), 7.50-7.43 (m, 4H), 4.25 (q, J = 6.0 Hz, 2H), 1.19 (t,
J = 6.8 Hz, 3H) ppm.
10. Yoshida, M; Saito, K; Fujino, Y; Doi, T. Tetrahedron, 2014, 70,
3452
11. Hsu, J-P; Wong, J-J; Ind. Eng. Chem. Res. 2006, 45, 2672
12. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494
13. Ko, K.; Nakano, K.; Watanabe, S.; Ichikawa, Y.; Kotsuki, H.
Tetrahedron Lett. 2009, 50, 4025
13C NMR (100 MHz, CDCl3): 174.7, 164.8, 161.4, 155.5, 137.8,
134.4, 130.2, 129.3, 129.0, 125.8, 125.7, 122.8, 118.3, 118.0, 61.9,
13.8 ppm.
MS (ESI): [M+ H+], Calcd. For: C18H14ClO4 (329.0575); Found:
329.0579.
14. Zhao, G.-L.; Huang, J. W.; Shi, M. Org. Lett. 2003, 24, 4737
15. Khan, A. T.; Lal, M; Ali, S.; Khan; M. M.; Tetrahedron Lett.
2011, 52, 5327.
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Tetrahedron. 2010, 66, 9629. (b) Dadwal, M.; Mobin, S. M.;
Namboothiri, I. N. N. Org. Biomol. Chem. 2006, 4, 2525. (c)
Meng, L.-G.; Li, C.-T.; Zhang, J.-F.; Xiao, G.-Y.; Wang, L. RSC
Adv. 2014, 4, 7109.
17. General procedure for the formation of 3-substituted flavone
derivatives (4aa-4am and 4ba-4bd): 4-hydroxycumarin (1
mmol), different derivatives of β-nitrostyrene (1 mmol), various
alcohols or amines (4 mmol) and DMAP (1 mmol) were taken in
a round bottom flask. The reaction mixtures were refluxed at 70-
80C. The completion of the reaction (directed by the
Ethyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate (4ab):
Yellow solid (0.249 g, 85%), mp 80-810C.
IR (KBr): 1729, 1638, 1567, 1436, 1396, 1089, 760 cm1.
1H NMR (400 MHz, CDCl3): 8.23 (d, J= 7.2 Hz, 1H), 7.73 (d, J =
7.2 Hz, 2H), 7.68 (d, J = 7.2 Hz, 1H), 7.56-7.45 (m, 4H), 7.42 (t,
J= 6.8 Hz, 1H), 4.25 (q, J = 6.8 Hz, 2H), 1.14(t, J = 7.2 Hz, 3H)
ppm.
13C NMR (100 MHz, CDCl3): 175.1, 165.1, 163.1, 155.8, 134.4,
131.9, 131.7, 128.8, 128.1, 126.1, 125.7, 123.2, 118.1, 61.9, 13.9
ppm.
MS (ESI): [M+ H+], Calcd. For: C18H15O4 (295.0965); Found:
295.0970
.

o
o
A wide range of 3-substituted carboxylate/carboxamide flavone derivatives were synthesized
from 4-hydroxycoumarin, β-nitrostyrene and alcohol/amine using multicomponent reaction in
presence of N,N-dimethyl-4-aminopyridine (DMAP).
Good yield, short reaction time, atom economy, cost effective and use of non-toxic organo-
catalyst are some of the remarkable advantages of the present protocol.