Synthesis of unsymmetrical 4-oxo-2-vinyl-4H-chromene-3-carbonitrile dyes via Knoevenagel reaction

Article abstract of DOI:10.1016/j.tetlet.2018.06.012

New 4-oxo-2-vinyl-4H-chromene-3-carbonitrile derivatives have been synthesized by the Knoevenagel reaction of 2-methyl-4-oxo-4H-chromene-3-carbonitrile with aromatic and heteroaromatic aldehydes. Spectral properties of the obtained compounds have been studied.

Full text of DOI:10.1016/j.tetlet.2018.06.012

Accepted Manuscript
Synthesis of unsymmetrical 4-oxo-2-vinyl-4H-chromene-3-carbonitrile dyes
via Knoevenagel reaction
K.S. Levchenko, K.A. Chudov, E.V. Zinoviev, K.A. Lyssenko, D.U. Demin,
N.O. Poroshin, P.S. Shmelin, E.P. Grebennikov
PII:
S0040-4039(18)30741-X
https://doi.org/10.1016/j.tetlet.2018.06.012
TETL 50050
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 March 2018
31 May 2018
4 June 2018
Please cite this article as: Levchenko, K.S., Chudov, K.A., Zinoviev, E.V., Lyssenko, K.A., Demin, D.U., Poroshin,
N.O., Shmelin, P.S., Grebennikov, E.P., Synthesis of unsymmetrical 4-oxo-2-vinyl-4H-chromene-3-carbonitrile
dyes via Knoevenagel reaction, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.012
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H-chromene-3-carbonitrile dyes via
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4
Knoevenagel reaction
K.S. Levchenko, K.A. Chudov, E. V. Zinoviev, D.U. Demin, K.A. Lyssenko, N.O. Poroshin, P. S. Shmelin, E.
P. Grebennikov.

1
Tetrahedron Letters
Synthesis of unsymmetrical 4-oxo-2-vinyl-4H-chromene-3-carbonitrile
dyes via Knoevenagel reaction
a
a
a
b
a
a
K.S. Levchenko , K.A. Chudov , E. V. Zinoviev , K.A. Lyssenko , D.U. Demin , N.O. Poroshin , P. S.
a
a
Shmelin , E. P. Grebennikov
a
JSC “Technomash”, 4 Ivana Franko St., Moscow 121108, Russia
N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 ul. Vavilova, 119991 Moscow, Russian Federation
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
New 4-oxo-2-vinyl-4H-chromene-3-carbonitrile derivatives have been synthesized by the
Knoevenagel reaction of 2-methyl-4-oxo-4H-chromene-3-carbonitrile with aromatic and
heteroaromatic aldehydes. Spectral properties of the obtained compounds have been studied.
2
009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
4
-Oxo-4H-chromene-3-carbonitrile
Knoevenagel reaction
Dyes
Chromophores

Corresponding author. Tel.: +7-985-188-6215; fax: + 7-499-144-8514; e-mail: k.s.levchenko@gmail.com

2
Over the past decades the development of organic dyes has
generated a huge interest owing to their potential applications in
a variety of areas: photoelectronics, nonlinear optical (NLO)
devices, information processing, fiber communications, optical
1-6
switching and information storage . They widely used as key
7
material for dye-sensitized solar cells , colorants in the industry,
8
in biological reactions, printing systems, food chemistry .
Benzopyrane dyes are widely used as a near-infrared fluorescent
9
dyes for rapid detection of hydrogen peroxide in living cells ,
1
0
quantification of alkaline phosphatase in living cells , near-
1
1
infrared fluorescent probe for biothiols
for hydrogen
12
polysulfides , as photoactive components in optical memory
1
3,14
devices , etc. The improvement of the properties of organic
dyes is carried out continuously. No matter in what field they are
applied. Dye molecules have been studied to improve the
efficiency of the solar energy to electricity conversion in dye-
sensitized solar cells, to improve nonlinear optical properties of
chromophores, to increase the sensitivity of analytical methods,
Scheme 1. Reagents and conditions: (i) DMF-DMA reflux, 1 h; (ii)
NH OH·HCl, EtOH, reflux, 2 h; (iii) NaOH, EtOH/H O (1:3), r.t., 24
2
2
o
o
h, AcOH, 0-10 C; (iv) MeCOCl, pyridine, 0-20 C, 2 h.
to
increase
stability
of
colorants,
etc.
In Knoevenagel reaction we found the problem of selectivity
of the reaction flow. It is known that chromone cycle is very
sensitive towards nucleophiles and bases, which cause ring-
The search for new acceptor or donor fragments for push-pull
dyes is one of the strategies of dyes development. Successful
combination of the donor and acceptor fragments connected by a
p-conjugated bridge (D-π-A) allows to achieve the necessary
physical and chemical properties of dyes such as optical
properties, solubility, thermal stability, etc.
1
5-16
opening reaction
Therefore we investigated organic bases
with different basicity and nucleophilicity. Organic bases such as
piperidine (Pip), tetraethylenediamine (TMEDA), and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were used as reaction
catalysts with ethanol and acetonitrile as solvents. The best
results were obtained in the case of Pip and TMEDA. The worst
yields were obtained with DBU. In all cases, several by-products
were formed. Lowering of the reaction temperature decreased by-
products formation but significantly increased time of the
process. Reactions proceeded more smoothly in the case of five-
membered heterocyclic aldehydes. The yields of reactions were
In this paper, the synthesis of new class of dyes based on 4-
oxo-4H-chromene-3-carbonitril-2-yl acceptor fragments is
considered. It should be noted, that there is no information about
the methods of preparation and optical properties of that dyes.
Therefore, studies in this area look very attractive. The results of
the research will open up access to a new class of dyes for NLO
devices and other applications.
55-87%.
The starting 2-methyl-3-cyanochromone was prepared
15
according to the method from 2-hydroxyacetophenone (Scheme
1
). In the first step, readily available 2-hydroxyacetophenone was
converted into the corresponding dimethylaminomethylene
derivative 2 in quantitative yield under reflux in DMF-DMA.
Compound 2 was then refluxed in ethanol with hydroxylamine
hydrochloride to give 2-(isoxazol-5-yl)phenol 3 in 80% yield.
Upon treatment with aqueous-ethanolic NaOH solution at room
temperature and neutralization of alkaline solution with acetic
acid, the isoxazole ring of compound 3 was cleaved to form 3-(2-
hydroxyphenyl)-3-oxopropionitrile (4) in 75% yield. Too fast
neutralization of alkaline solution with acetic acid at high
o
temperatures (>10 C) led to undesirable by-product 6. 2-Methyl-
4
-oxo-4H-chromene-3-carbonitrile (5) was prepared by
optimized method of acylation of 4 with acetyl chloride at 0-20
°
C. The introduction of the donor fragments into position 2 of the
2
-methyl-4-oxo-4H-chromene-3-carbonitrile (5) was carried out
under Knoevenagel reaction conditions. Aldehydes 7 a-h were
used as model compounds for investigation of 2-methyl-4-oxo-
4H-chromene-3-carbonitrile (5) reactivity (Scheme 2).
3
Scheme 2. Reagents and conditions (i) EtOH or CH CN, catalyst,
r.t.-reflux, 1,5 h - 5 d.
The worst results were obtained in the cases of 4-fluoro-, 4-
chloro- and 4-bromo- benzaldehydes 7 f-h. The title compounds
8
f-h were obtained in 20-42% yields. Amino derivatives 8 i-m
were obtained in moderate to good yields. All of isolated
compounds were only in the trans form. The structure of 8k was
confirmed by XRD with all atoms of conjugated system lining in
one plane (Figure 1).

3
The results of Knoevenagel reactions are presented in Table 1.
It should be noted that reaction speed and yields were not reliant
directly on the aldehydes reactivity. That can be explained by
occurrence of several side reactions which colorless and slightly
colored by-products were detected by TLC analysis. Obviously,
these substances were the by-products of the benzopyranes cycle
The authors suggested that it is entirely possible for 3-acyl
flavones to transform into tri- and diketones (similar to the
Baker-Venkataraman reaction) via ring opening reaction
followed by cyclization back into flavone.
destruction
of
2-methyl-4-oxo-4H-chromene-3-carbonitrile
followed by reaction with aldehydes (Scheme 3).
Scheme 3. Reagents and conditions (i) 7l, EtOH, piperidine, reflux,
6
h.
To confirm the above hypothesis in our case, we isolated and
analyzed the uncolored by-product from synthesis of 8l. In this
reaction, we observed the greatest amount of by-products and the
minimum yield of the desired compound 8l. H, C, HRMS and
XRD (Figure 2) analyses confirmed the structure 9 shown in
Scheme 3.
Figure 1. The general view of 8k in representation of atoms by
thermal ellipsoids (p = 50%).
1
13
Similar behavior was observed in the case of 3-acyl flavones.
On heating under reflux with an aqueous solution of 5%
potassium carbonate, 3-acyl flavones produce flavones with
1
7
moderate yields .
a
Table 1. Reagents and conditions of Knoevenagel reaction
о
Compound
Catalyst
Time
Temperature Yield %
M.p. С
Pip
TMEDA
DBU
Pip
TMEDA
Pip
TMEDA
Pip
TMEDA
5 d
5 d
5 d
3 h
r.t
r.t
r.t.
reflux
reflux
reflux
reflux
reflux
reflux
74%
72%
<10%
62%
55%
65%
87%
65%
55%
8
a
180-182
1
56-158
8
b
b
5 h
1,5 h
8
c
237-238
224-226
b
5 h
4 h
8
d
b
5 h
8
e
f
Figure 2. The general view of 9 in representation of atoms by
thermal ellipsoids (p=50%).
Pip
pip
3 h
reflux
reflux
75%
20%
252-254
226-228
8
36 h
In the case of reaction of 2-methyl-4-oxo-4H-chromene-3-
carbonitrile (5) with 7c another highly colored product was
observed. We proposed it to be the by-product of the reaction of
the in situ formed 2-[2-(5-bromo-furan-2-yl)-vinyl]-4-oxo-4H-
chromene-3-carbonitrile with piperidine used as catalyst. It was
confirmed by reaction of isolated 8c with an excess of piperidine
Pip
TMEDA
Pip
pip
TMEDA
Pip
28 h
12 h
28 h
5 d
reflux
r.t
reflux
r.t
42%
22%
40,6%
28.4%
23%
8
8
g
2
43-245
h
c
10 h
reflux
235-237
214
8
h
reflux
27%
(
3
CH CN)
(Scheme 4).
8
8
i
Pip
Pip
Pip
2 h
reflux
reflux
reflux
reflux
67%
80%
j
d
4 h
10 h
6 h
254-256
>250
8
k
56,7%
23%
8
l
-
Pip
Pip
8
m
b
219-220
1
3 h
reflux
68,7%
(
3
CH CN)
a
General reaction conditions. One drop of catalyst was added to a mixture of
2
-methyl-4-oxo-4H-chromene-3-carbonitrile 5 (185 mg, 0,1 mmol) and
Scheme 4. Reagents and conditions (i) EtOH, piperidine, reflux.
3
aldehyde 7 a-m (0,1 mmol) in ethanol or CH CN. After stirring at appropriate
The absorption and fluorescence spectral data of the synthesized
products 8a-m are summarized in Table 2. Groups of compounds
8a-e and 8f-h have insignificant fluorescence and absorption in
UV area due to a weak donor substituent in position 2 of 4-oxo-
4H-chromene-3-carbonitrile. Compounds 8i-m with stronger
donor substituents have absorption maxima at 474-513 nm and
temperature and time, the precipitate that formed was filtered off, washed
with ethanol, and dried in air. In case of absence of a solid precipitate the
solvent was distilled off under reduced pressure. The residue was separated
by column chromatography.
b
Mixture was first stirred for three days at room temperature.
Mixture was first stirred for two days at room temperature.
Mixture was first stirred for 14 h at room temperature.
c
d

4
strong fluorescence at 547-580 nm. All the compounds are
characterized by a large Stokes shift (60-103 nm). Compound 10
has the smallest Stokes shift value among the obtained
compounds and absorption maxima at 536 nm.
Table 2. The absorption and fluorescence spectral data and
molecular hyperpolarizability (β) estimated at M052X/ 6-
3
1+G(d) level for of the synthesized products 8a-m and 10
abs
5
em
max
fl d
e
Compound

ε*10

SS
I
fl
φ
β (a.u.)
-
1
-1
(
nm) (M .cm ) (nm) (nm)
(a.u.)
23
b
8
a
406
0,39
0,27
1,14
0,63
0,35
0,41
0,23
0,17
0,25
0,11
0,56
0,40
0,41
0,18
496
452
90
60
-
-
c
b
c
c
8
8
b
382
392
380
392
348
350
352
487
474
513
510
500
536
20
-
-
c
493 101
22
-
-
-
Figure 4. Fluorescence spectra of 8d, 8i-m, 10 in chlorobenzene at
concentrations 0,003 mg/ml. The fluorescence excitation
wavelengths are at the maximum of absorption.
8
d
469
480
-
89
78
-
31
-
8
e
18
-
-
c
8
f
-
-
-
Solvatochromism was investigated for compounds 8k-m in
solvents of low (dioxane, chlorobenzene, methylene chloride)
c
c
8
8
g
-
-
-
-
5005
-
and high polarity (acetone, acetonitrile).
A
positive
h
-
-
-
-
solvatochromism was observed in low-polarity solvents for
compounds 8k-m, while in high-polarity solvents they displayed
an anomalous solvatochromism. In other words, in a low regime
c
8
8
i
547
60
329
491
958
524
242
200
0,15
0,34
0,25
0,20
0,20
0,18
15432
20493
16186
14568
15645
12819
c
c
j
577 103
8
k
571
574
564
572
68
64
64
36
of solvent polarity such as from 1,4-dioxane (E
dichloromethane (E (30) = 40,7), absorption area is red-shifted
25-27 nm) with increasing solvent polarity, whereas in a higher-
polarity acetone (ET(30) = 42.2) or acetonitrile (E (30) = 45.6)
T
(30) = 36.0) to
c
T
8
l
(
c
8
m
T
c
1
0
absorption area is blue-shifted (5-10 nm) relative to that in
dichloromethane (Figure 5).
a
abs
em
λ
, and λ are the wavelengths of the maxima of the absorption bands, and
fluorescence spectra of compounds 8a-l, respectively; ε - molar extinction
fl
coefficient; SS - Stokes shift; φ is the fluorescence quantum yield;
max
I
fl
- fluorescence intensity at the maximum of the fluorescence band of
compounds 8a-l.
b
em
Solution in DMSO (λ at c = 0,003 mg/ml);
c
em
Solution in chlorobenzene (λ at c = 0,003 mg/ml).
d
The fluorescence quantum yield was determined using a relative optical
1
8
method .
e
β is the calculated using M052X functional and 6-31+G(d) basis set first
hyperpolarizability.
Figures 3 and 4 show the absorption and fluorescence spectra of
the compounds 8d, i-m and 10. It was found that obtained
compounds have similar spectral properties with dimethyl-[4-(4-
nitro-phenylazo)-phenyl]-amine (DR1) or tricyanovinylidene-
diphenylaminobenzene (TCVDPA) derivatives, that are used as
1
,19,20
electro-optic chromophores in NLO devices
.
Figure 5. Absorption spectra of 8k in different solvents (c = 0,05
mg/ml).
Fluorescence area (Figure 6) for all of compounds is red-shifted
with increasing solvent polarity from 1,4-dioxane to acetonitrile
(35-42 nm). This may indicate that the excited state of
chromophores has larger dipole moment than in the ground state.
And larger shift of the emission to lower energy is due to
stabilization of the excited state by the more polar solvent
molecules. It is interesting to note that fluorescence quenching is
observed in polar solvent (acetone or acetonitrile).
The first hyperpolarizability (β) for 8h-8m and 10 molecules
was calculated using M052X functional and 6-31+G(d) basis set
(see SI) that were shown to be adequate for calculation of
conjugated molecules consisted from different
21-24
building blocks . The results show that value of β for
calculated molecules is 2-3 times higher than that for 4,4'-
2
5
hydroxy-nitrostilbene (HONS) , and more than order of
magnitude higher than that of pNA that is standard benchmark
Figure 3. Absorption spectra of 8d in DMSO (c = 0,05 mg/ml), 8i in
chlorobenzene (c = 0,2 mg/ml); 8j in chlorobenzene (c = 0,25
mg/ml); 8k,l,m in chlorobenzene (c = 0,05 mg/ml) and 10 in DMSO
2
6
NLO molecule . It is noteworthy that β values are proportional
abs
to 
.
(
c = 0,05 mg/ml).

5
9
1
1
1
1
.
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Figure 6. Fluorescence spectra of 8k in different solvents (c = 0,003
mg/ml).
1
1
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In conclusion, we have developed efficient methods of synthesis
and modification of new 4-oxo-2-vinyl-4H-chromene-3-
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4
-oxo-4H-chromene-3-carbonitrile
with
aromatic
and
1
1
heteroaromatic aldehydes. Experimental solvatochromic data and
calculated first hyperpolarizability (β) of obtained chromophores
demonstrates the prospects of their use in NLO devices and other
applications.
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Acknowledgments
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This work was supported by RSF 17-73-10433. The X-ray
diffraction data were obtained using the equipment of Center for
molecules composition studies of INEOS RAS.
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Supplementary data containing methods of synthesis and
characterization data of synthesized compounds (2-6, 7j-m, 8a-
m, 9 and 10), solvatochromism investigation as well as details of
DFT calculations are available online. Crystallographic data for
the structures reported in this paper have been deposited to the
Cambridge Crystallographic Data Centre as supplementary no.:
CCDC - 1828944 (for 8k) and CCDC - 1828945 (for 9). These
data can be obtained free of charge from The Cambridge
Crystallographic Data via www.ccdc.cam.ac.uk/data_request/cif.
5
6
.
.
7
8
.
.

6
Methods of synthesis of new chromophores by the Knoevenagel
reaction were developed
Side process in Knoevenagel reaction was found
New potential chromene based non-linear optical (NLO) dyes
were prepared
New acceptor fragment for push-pull dyes was developed