New approach to synthesis of 4-arylcoumarin derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.09.111

A simple and highly efficient new approach for the synthesis of 4-aryl-2-oxo-2H-chromene-3-carbonitriles based on the oxidation and hydrolysis of 2-amino-4-aryl-4H-chromene-3-carbonitriles is described.

Full text of DOI:10.1016/j.tetlet.2015.09.111

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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New approach to synthesis of 4-arylcoumarin derivatives
a
a
b
Ivan N. Bardasov a, , Anastasiya U. Alekseeva , Oleg V. Ershov , Marina D. Surazhskaya ,
⇑
Andrei V. Churakov b, Dmitry A. Grishanov b
a Ulyanov Chuvash State University, Moskovsky pr. 15, Cheboksary 428015, Russia
b Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskii prosp. 31, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and highly efficient new approach for the synthesis of 4-aryl-2-oxo-2H-chromene-3-carboni-
triles based on the oxidation and hydrolysis of 2-amino-4-aryl-4H-chromene-3-carbonitriles is described.
Ó 2015 Published by Elsevier Ltd.
Received 13 April 2015
Revised 13 August 2015
Accepted 24 September 2015
Available online xxxx
Keywords:
Heterocyclic compounds
Cyano compounds
Coumarin
Knoevenagel condensation
Michael addition
Coumarins are an important class of oxygen-containing hetero-
cycles. The 2H-chromen-2-one (coumarin) fragment is known to
be a part of many biologically active compounds,1 possessing anti-
inflammatory,1a,b antioxidant,1c–e antimicrobial,1f antiviral,1g–i
anticancer,1j,k and antiproliferative1l activities. Additionally, good
photochemical properties, chemical stability, and ease of
synthesis make coumarin derivatives an important class of
fluorescent probes for biological studies.2 Coumarin chromophores,
which can be used as light removable protecting groups in caged
compounds, have been used as light-removable protecting groups,
so-called ‘caging groups’, and applied in the optical control of bio-
logical processes.3 Generally, coumarins are synthesized utilizing
the Perkin, Pechmann, Wittig, and Reformatsky reactions,4a–g
Knoevenagel condensation reactions,4h,i as well as other cycliza-
tion reactions.4j,k The most common method for the synthesis of
cyano-containing 4-arylcoumarin derivatives is the Knoevenagel
Ar
CN
O
+
Ar
H
,
]
X
O
O
[
CN
2
B
r2
Ar
X
O
NH2
Br
CN
1
HO
O
O
Br
3
Scheme 1. Oxidation of 2-amino-4H-chromenes 1a–o into coumarin derivatives
2a–o and 3a–c.
Ar
H
Ar
O
CN
CN
CN
condensation
between
substituted
benzophenones
and
+
-H2O
cyanoacetic acid or its esters4h,i or the reaction between 3-aryl-2-
cyanoacrylic acid esters and phenols with subsequent oxidation.5
In this Letter, we describe a new approach to 4-arylcoumarin
derivatives based on the oxidation and hydrolysis of 4-aryl-2-
amino-4H-chromenes 1, leading to formation of 4-aryl-2-oxo-2H-
chromene-3-carbonitriles 2a–o6 and 3a–c7 (Scheme 1).
X
OH
X
O
NH2
1
78-94 %
Ar
Ar
Ar
+H2O/H+
-NH4+
CN
NH
CN
NH
CN
O
[O]
X
O
X
O
X
O
2-Amino-4-aryl-4H-chromene-3-carbonitriles (1a–o) were
synthesized according to literature procedures via the three-
A
2
B
Scheme 2. Oxidation and hydrolysis of 2-amino-4H-chromenes 1a–o into
coumarin derivatives 2a–o.
⇑
Corresponding author. Tel.: +7 9083030163; fax: +7 8352450279.
E-mail address: bardasov.chem@mail.ru (I.N. Bardasov).
http://dx.doi.org/10.1016/j.tetlet.2015.09.111
0040-4039/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Bardasov, I. N.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.111

2
I. N. Bardasov et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
Synthesis of 4-aryl-2-oxo-2H-chromene-3-carbonitriles 2a–oa
Entry
Substrate
Product
Yieldb (%)
CN
O
CN
1
62
HO
Cl
O
NH2
HO
Cl
O
2a
1a
CN
CN
O
2
3
73
81
HO
O
NH2
HO
O
1b
2b
O2N
O2N
CN
CN
O
HO
O
NH2
HO
O
1c
2c
OMe
OMe
4
5
71
73
CN
NH2
CN
HO
O
HO
O
O
1d
2d
OMe
OMe
MeO
OMe
MeO
OMe
CN
CN
O
HO
O
NH2
HO
HO
O
1e
2e
O
O
CN
O
CN
6
7
57
76
HO
O
NH2
O
1f
2f
CN
CN
O
NH2
O
O
2g
1g
Cl
Cl
CN
O
CN
8
9
64
68
O
O
NH2
1h
2h
OMe
OMe
CN
CN
O
O
O
NH2
1i
2i
C6H13
C6H13
O
O
10
11
70
51
CN
CN
O
O
NH2
O
1j
2j
O
O
CN
CN
O
O
NH2
O
1k
2k
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I. N. Bardasov et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 1 (continued)
Entry
Substrate
Product
Yieldb (%)
CN
CN
O
12
13
82
O
NH2
O
1l
2l
Cl
Cl
CN
CN
75
80
O
NH2
NO2
O
O
1m
2m
NO2
14
CN
CN
O
O
NH2
O
1n
2n
OMe
OMe
15
82
CN
CN
O
NH2
O
O
2o
1o
a
Reaction conditions: compound 1 (10 mmol), I2O5 (2 mmol), CH3COOH (15 mL), H2O (5 mL), 70 °C, 20 min.
Yield of isolated product.
b
component condensation reaction of various phenols, arylaldehydes,
and malononitrile in ethanol under basic conditions.8 Hydrogen
peroxide, selenium dioxide, chromium trioxide, oxygen, bromine
and iodine pentoxide were all examined as oxidants for the synthe-
sis of coumarin derivatives 2a–o, with the best results being
obtained using iodine pentoxide. The reaction was postulated to
involve tautomerization of 1 into intermediate A followed by oxi-
dation to give iminopyran B, which upon acid-catalyzed hydrolysis
Ar
Ar
Ar
O
Br
CN
NH
CN
CN
NH
+Br2
-HBr
HO
O
NH2
HO
O
HO
1
A
Ar
Ar
Ar
Br
CN
NH
CN
NH
Br
HO
CN
+2Br2
-2HBr
+H2O/H+
-NH4+
HO
O
HO
O
O
O
Br
3
B
C
Br
Scheme 3. Synthesis of 4-aryl-6,8-dibromo-7-hydroxy-2-oxo-2H-chromene-3-car-
bonitriles 3a–c.
Table 2
Synthesis of 4-aryl-6,8-dibromo-7-hydroxy-2-oxo-2H-chromene-3-carbonitriles 3a–
ca
Entry
1
Substrate
Product
Yieldb (%)
CN
Br
CN
O
85
HO
Cl
O
NH2
HO
O
1a
Br 3a
Cl
CN
Br
CN
O
2
3
82
78
HO
O
NH2
HO
O
Br 3b
O2N
1b
O2N
CN
Br
CN
O
HO
O
NH2
HO
O
1c
Br 3c
a
Reaction conditions: compound 1 (10 mmol), Br2 (30 mmol), CH3COOH (20 mL),
60 °C, 1 h.
b
Figure 1. ORTEP diagram of 1-(2-chlorophenyl)-3-oxo-3H-benzo[f]chromene-2-
carbonitrile (2m).
Yield of isolated product.
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4
I. N. Bardasov et al. / Tetrahedron Letters xxx (2015) xxx–xxx
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formed the 4-aryl-2-oxo-2H-chromene-3-carbonitriles 2a–o in
51–82% yields (Scheme 2 and Table 1).
Using bromine as the oxidizing agent caused dibromination of
the phenyl ring during oxidation leading to the formation of com-
pounds 3a–c. This reaction was proposed to involve the bromina-
tion of intermediate A and subsequent dehydrohalogenation to
iminopyran B. Following electrophilic bromination, intermediate
C can be hydrolysed to yield 4-aryl-6,8-dibromo-7-hydroxy-2-
oxo-2H-chromene-3-carbonitriles 3a–c in 78–85% yields (Scheme 3
and Table 2).
The structures of compounds 2a–o and 3a–c were confirmed by
IR, 1H and 13C NMR spectroscopy, mass spectrometry6,7 and by sin-
gle crystal X-ray diffraction analysis of compound 2m (Fig. 1).9
In conclusion, there are several articles in the literature that
describe the synthesis of 4-arylchromene-3-carbonitriles from
4-aryl-2-amino-4H-chromenes,10 but detailed research in this area
has not been carried out. In this Letter, we report a novel, opera-
tionally simple approach for the synthesis of coumarin derivatives.
Future work regarding the expansion of this reaction is currently in
progress.
5. (a) Sabry, N. M.; Mohamed, H. M.; Khattab, E. Sh. A. E. H.; Motlaq, Sh. S.; El-
Agrody, A. M. Eur. J. Med. Chem. 2011, 46, 765–772; (b) Kemnitzer, W.; Jiang, S.;
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6. Typical procedure for the preparation of 4-aryl-2-oxo-2H-chromene-3-
carbonitriles 2: 2-Amino-4H-chromenes 1 (10 mmol) and I2O5 (2 mmol) in a
mixture of CH3COOH (15 mL) and H2O (5 mL) was stirred at 70 °C for 20 min.
After cooling, H2O (40 mL) was added, and the precipitate was filtered and
washed with H2O (20 mL). Compound 2a. Mp 175–176 °C (dec); 1H NMR
(500.13 MHz, DMSO-d6): d 6.84–6.88 (2H, m, 2CH), 7.12 (1H, d, J = 8.7 Hz, CH),
Acknowledgement
This research was supported by the Presidential Grant of the
Russian Federation for Young Scientists (MK-6312.2015.3).
7.52–7.55 (2H, m, C6H5), 7.63–7.65 (3H, m, C6H5), 11.38 (1H, br s, OH). 13C NMR
0
(125.76 MHz, DMSO-d6): 96.03 (C3), 102.75 (C8), 110.49, 114.78 (C4
,
C6),
114.62 (CN), 128.29, 128.70, 128.78, 130.45, 132.38 (C5, C6H5), 155.87, 157.66
0
Supplementary data
(C8 , C2), 163.56, 164.60 (C7, C4). IR (mineral oil, cmꢀ1): 2221 (CN), 1695 (C@O).
MS (EI, 70 eV): m/z (%) 263 [M]+ (100), 235 [Mꢀ28]+ (80). Anal. Calcd for
C16H9NO3: C, 73.00; H, 3.45; N, 5.32. Found: C, 73.09; H, 3.46; N, 5.40.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
111.
7. Typical procedure for the preparation of 4-aryl-6,8-dibromo-7-hydroxy-2-oxo-2H-
chromene-3-carbonitriles 3: Br2 (30 mmol) was added to 2-amino-4H-
chromenes 1 (10 mmol) in CH3COOH (20 mL) and heated at 60 °C for 1 h.
After cooling, H2O (20 mL) was added, and the precipitate was filtered and
washed with a mixture of H2O (15 mL) and i-PrOH (5 mL). Compound 3a. Mp
290–291 °C (dec); 1H NMR (500.13 MHz, DMSO-d6): d 4.40 (1H, br s, OH), 7.22
References and notes
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40
(125.76 MHz, DMSO-d6): 98.22 (C3), 100.45 (C6), 109.07, 112.97 (C
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80
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Please cite this article in press as: Bardasov, I. N.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.111