Reactions of 2-(trifluoromethyl)chromones with cyanoacetamides, ethyl cyanoacetate and diethyl malonate. Unexpected synthesis of benzo[c]coumarin derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.09.082

While 2-(trifluoromethyl)chromones react with cyanoacetamides in the presence of sodium ethoxide to produce 6-(2-hydroxyaryl)-4-(trifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carbonitriles, their reactions with ethyl cyanoacetate and diethyl malonate unde

Full text of DOI:10.1016/j.tetlet.2011.09.082

Tetrahedron Letters 52 (2011) 6271–6274
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Tetrahedron Letters
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Reactions of 2-(trifluoromethyl)chromones with cyanoacetamides,
ethyl cyanoacetate and diethyl malonate. Unexpected synthesis
of benzo[c]coumarin derivatives
Vyacheslav Ya. Sosnovskikh a, , Alexander V. Safrygin a, Viktor A. Anufriev a, Oleg S. Eltsov b,
⇑
Viktor O. Iaroshenko c
a Department of Chemistry, Ural State University, pr. Lenina 51, 620083 Ekaterinburg, Russia
b Department of Chemistry, Ural Federal University, St. Mira 19, 620002 Ekaterinburg, Russia
c Institut für Chemie, Universität Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2011
Revised 31 August 2011
Accepted 16 September 2011
Available online 29 September 2011
While 2-(trifluoromethyl)chromones react with cyanoacetamides in the presence of sodium ethoxide to
produce 6-(2-hydroxyaryl)-4-(trifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles, their reac-
tions with ethyl cyanoacetate and diethyl malonate under the same conditions took an entirely different
course and gave novel functionalized derivatives of 6H-benzo[c]chromen-6-one.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chromones
Active methylene compounds
2-Pyridones
6H-Benzo[c]chromen-6-one
Trifluoromethylated heterocycles
Chromones (4H-chromen-4-ones, 4H-1-benzopyran-4-ones)
are naturally occurring oxygen-containing heterocyclic com-
pounds which perform important biological functions in nature.1
Many natural and synthetic chromone derivatives, including
2-methylchromones, exhibit various types of biological activities
(antiviral, antiallergic, neuroleptic, anti-inflammatory, and antitu-
mor)2 and find use as valuable synthetic intermediates in the
preparation of pharmacologically relevant products and new het-
erocyclic systems.3 These compounds possess two strong electro-
philic centers (carbon atoms C-2 and C-4 of the chromone
system) and their reactions with dinucleophiles start predomi-
nantly with an attack of the C-2 atom (1,4-addition) and are
accompanied by pyrone ring-opening to form an intermediate
capable of undergoing intramolecular heterocyclizations.4 Alterna-
tively, the initial attack can also occur at C-4 (1,2-addition).5
Most pertinent to the present researchare thereactions involving
the addition of active methylene compounds to 2-alkylchromones.
However, to the best of our knowledge, very little is known on this
topic. In almost all cases, the reactions proceeded without cleavage
of the pyrone ring and only 1,2-addition (Knoevenagel condensa-
tion) at the carbonyl group took place to give the corresponding
methylidene derivatives.5 There are only two reports on the reac-
tions of 2-methylchromones (1) with malononitrile, cyanoacet-
amide, and ethyl cyanoacetate leading to products which can
result from the initial nucleophilic 1,2- or 1,4-additions. Zeid et al.6
investigated the addition of malononitrile (sodium ethoxide, etha-
nol) and ethyl cyanoacetate (piperidine, benzene) to the carbonyl
group of 1 (R = H) and obtained the methylidene derivatives 2.
Recently,7 the reaction of 1 with malononitrile, cyanoacetamide,
and ethyl cyanoacetate in the presence of sodium ethoxide, leading
to the isolation of 2-pyridones 3 and 2-pyrones 4, was reported. In
this case, the reaction proceeded via nucleophilic 1,4-addition with
concomitant opening of the pyrone ring and subsequent intramolec-
ular cyclization (Scheme 1).
It is known that 2-alkylchromones are less reactive than
2-unsubstituted chromones due to steric and electronic factors,
however, the introduction of electron-withdrawing RF groups at
the 2-position of the chromone system significantly changes the
reactivity of the pyrone ring with respect to nucleophiles, and pro-
vides broad synthetic potential for 2-(polyfluoroalkyl)chromones.8
In recent years, these compounds have attracted considerable
attention as highly reactive substrates, which can serve as the
starting materials in the synthesis of various partially fluorinated
heterocycles with useful properties due to the enhanced electro-
philicity of the C-2 atom, which is usually attacked first in reac-
tions with N-, S-, and C-nucleophiles.9 Among the diverse
⇑
Corresponding author. Fax: +7 343 261 59 78.
E-mail addresses: sosn1951@mail.ru, vyacheslav.sosnovskikh@usu.ru (V.Ya.
Sosnovskikh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.082

6272
V. Ya. Sosnovskikh et al. / Tetrahedron Letters 52 (2011) 6271–6274
Me
CF3
NC
X
CN
O
X
CO2Et
CN
O
R
N
H
OH
N
R'
O
Me
O
CF3
OH
3
2 (X = CN, CO2Et)
6 (X = CN, CO2Et)
7a (R' = H), 7b (R' = Me),
7c (R' = NH2)
ref. 6
R = H
NCCH X
-H2O
(i,ii)
2
ref.10
R = H
XCH2CO2Et,
TiCl4
O
O
O
Me
R
R
CN
CONHR'
CN
NCCH2X (i)
ref. 7
Me
O
O
X
OH
NCCH2CONHR'
EtONa,
CF3
R
1 (R = H, Me)
A (X = CONH2, CN)
R = H
O
CF3
OH
A
5
ref. 7
NCCH CO Et
(i)
2
2
Me
XCH2CO2Et,
EtONa
X = CN
X = CO2Et
CN
OH Me
R
R
CN
CF3
CF3
O
O
9
CN
CO2Et
OH
8
-EtOH
10
CO2Et
OH
OH
1
10a
6
7
10b
R
B
4
2
OH
6a
R
Scheme 1. Reagents and conditions: (i) EtONa, EtOH, reflux;6,7 (ii) piperidine,
3
4a
O
NH
O
O
4
benzene, reflux (X = CO2Et).6
8a (R = H), 8b (R = 2-Me),
8c (R = 3-MeO), 8d (R = 1,3-Me2)
9a (R = H), 9b (R = Me),
9c (R = Cl)
transformations of 2-(trifluoromethyl)chromone (5, R = H), one of
the most interesting is its TiCl4-mediated Knoevenagel condensa-
tion with ethyl cyanoacetate and diethyl malonate to give methyl-
idene derivatives of 4H-chromene 6 in good yields (Scheme 2).10
In the continuation of our studies on the chemical properties of
chromones 5,8,9 we investigated their reactions with active meth-
ylene compounds, such as cyanoacetamides, ethyl cyanoacetate,
and diethyl malonate, under classical conditions (sodium ethoxide,
ethanol, reflux). Herein, we report that, in contrast to 2-methylchr-
omones, condensation of 2-(trifluoromethyl)chromones with ethyl
cyanoacetate and diethyl malonate represents a one-pot, multi-
step transformation and can be employed to obtain the functional-
ized 6H-benzo[c]chromen-6-ones (benzo[c]coumarins). Recently
reported syntheses of this skeleton, which are present in a number
of pharmacologically relevant natural products, such as autumna-
riol,11 autumnariniol,12 alternariol,13 and altenuisol,14 rely on
sequential [3+3]-cycloaddition–Suzuki cross-coupling reactions,15
Me3SiOTf-mediated condensation of 1,3-bis(silyl enol ethers) with
chromones followed by domino retro-Michael-aldol-lactonization
reactions,16 reactions of chromones with dimethyl 1,3-acetonedi-
carboxylate,17 and 4-chloro-3-formylcoumarin with 1,3-bis(silyl
enol ethers)18 and 1,3-dicarbonyl compounds.19 However, the sub-
stitution pattern present in our products is, to the best of our
knowledge, not available via these transformations.
We found that 2-(trifluoromethyl)chromone (5, R = H) reacts
with cyanoacetamide, N-methyl cyanoacetamide, and cya-
noacetohydrazide on refluxing in absolute ethanol in the presence
of sodium ethoxide, affording novel 6-(2-hydroxyphenyl)-2-oxo-
4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitriles 7a–c in
55–74% yields. This reaction is an earlier known transformation of
2-methylchromones (Scheme 1),7 which can be regarded as nucleo-
philic 1,4-addition of cyanoacetamides with the formation of a new
C–C bond (intermediate A) followed by cyclodehydration to the
products 7 (Scheme 2). It is worth noting that compound 7a can also
be obtained from 5 and malononitrile in 81% yield.
Scheme 2. Synthesis of compounds 7–9.
that is, 3-cyano-4-(trifluoromethyl)-6-substituted 2-pyridones. In
our case, the choice between 4-CF3- and 6-CF3-2-pyridones was
made in favor of the former on the basis of the 13C NMR spectrum
3
of 7b (C-3: 97.0 ppm, q, JC,F = 2.2 Hz; C-5: 103.8 ppm, q,
2
3JC,F = 4.4 Hz; C-4: 143.9 ppm, q, JC,F = 33.0 Hz). The assignment
of all the signals was achieved using 2D 1H–13C HSQC, and HMBC
experiments.22
As 2-methylchromones have been shown7 to react with ethyl
cyanoacetate in the presence of sodium ethoxide to give 6-(2-
hydroxyaryl)-4-methyl-2-oxo-2H-pyran-3-carbonitriles 4 (Scheme
1), it was expected that Michael addition of ethyl cyanoacetate to
chromones 5, followed by a ring-opening–ring-closure sequence
would provide a direct route to the hitherto unknown 6-(2-
hydroxyaryl)-4-(trifluoromethyl)-2-oxo-2H-pyran-3-carbonitriles
(4 with a CF3 group at the 4-position instead of a methyl group).
However, it turned out that under these conditions (EtONa, EtOH,
reflux, 12 h), chromones 5 reacted with two molecules of ethyl
cyanoacetate, yielding 7-hydroxy-6-imino-9-(trifluoromethyl)-
6H-benzo[c]chromene-8-carbonitriles 8a–d as the only isolated
products in 35–66% yields (reaction conditions were not opti-
mized).23 This outcome was rather unexpected and indicated that
the reaction of 5 with ethyl cyanoacetate took an entirely different
course compared with the reaction of 1. In this process ethyl
cyanoacetate may be regarded as a synthetic equivalent of 1,3-dic-
yanoacetone, which is not a readily available compound.
A similar base-mediated reaction of 5 with diethyl malonate
followed the same 1:2 stoichiometry and gave 7-hydroxy-6-oxo-
9-(trifluoromethyl)-6H-benzo[c]chromene-8-carboxylates 9a–c in
37–62% yields (Scheme 2).24 Note that coumarin 9a was also
obtained from 5 and diethyl 1,3-acetonedicarboxylate, albeit in a
lower yield. These results are of particular interest because the for-
mation of 6H-benzo[c]chromen-6-one derivatives, also known as
In this context, two Letters are of interest when trifluoromethy-
lated 1,3-diketones are reacted with cyanoacetamide20 and
N-methyl cyanoacetamide21 to give, regioselectively, one isomer,
benzo[c]coumarins or dibenzo-
chromones has not been reported to date.
a
-pyrones,25 from 2-substituted

V. Ya. Sosnovskikh et al. / Tetrahedron Letters 52 (2011) 6271–6274
6273
The structures of compounds 8 and 9 were confirmed by spectro-
scopic data, including IR, NMR (1H, 19F, and 13C), and elemental anal-
ysis; assignmentof all thesignals was accomplishedbased onresults
from 2D 1H–13C, HSQC, and HMBC experiments. In the 1H NMR spec-
tra of compounds 8a–d and 9a–c in DMSO-d6, the most downfield
shifted signals were assigned to the OH proton (d 8.0–8.3 for 8 and
11.6–11.8 for 9), H-1 (d 8.21–8.38 for 8 and 8.29–8.54 for 9), and
H-10 (d 7.73–7.80 for 8 and 7.99–8.17 for 9). The position of the
OH signal can be explained by the intramolecular hydrogen bond
present in 9. In the 19F NMR spectra the CF3 group manifests itself
at ꢀ63.1 to ꢀ63.5 ppm for 8a–d and ꢀ60.0 ppm for 9a–c. The most
informative and strong cross-peaks in the 2D HMBC spectra for 9a
are as follows: H-10/C-6a, H-10/C-10b, H-10/C-8, H-10/CF3, H-10/
C-6, H-10/CO2Et, H-1/C-3, H-1/C-10a, H-1/C-4a. In the IR spectra of
compounds 8 and 9, a highly characteristic nitrile absorption at
2220–2225 cmꢀ1 and carbonyl bonds at 1720–1741 and 1679–
1682 cmꢀ1, respectively, were observed.
For the formation of products 8 and 9 a plausible mechanism is
depicted in Scheme 3. There are two possible routes to these com-
pounds. In the first (path a), initial nucleophilic attack of the
base-activated methylene compound at C-2 followed by Claisen
condensation (intermediate A, the initial Claisen self-condensation
of the starting ester could not be excluded), intramolecular cycliza-
tion, and dehydration (intermediate B), and then by aromatization
(after hydrolysis and decarboxylation) leads to compounds 8 or 9
through the involvement of phenolic hydroxy group. The second
route (path b) implies initial double nucleophilic attack at the
electrophilic C-2 and C-4 atoms (intermediate C) followed by intra-
molecular cyclization (intermediate D), aromatization, and lacton-
ization (Scheme 3). As diethyl 1,3-acetonedicarboxylate can be
used in this multi-step transformation, we believe that ‘path a’ is
more preferred. The formation of 3,4-benzoannulated coumarins 8
and 9 is strictly linked to their high thermodynamic stability which
represents the driving force of the process. Clearly, the most signif-
icant difference between the reactions of chromones 5 with cya-
noacetamides, and related reactions with the other compounds
containing an active methylene group, such as ethyl cyanoacetate
and diethyl malonate, is the failure of cyanoacetamides to form
1:2 adducts. This failure may be attributed to the readiness with
which 1:l adducts undergo ring closure involving the amide group
to form 2-pyridones 7.
In conclusion, we have shown, for the first time, that the con-
densation of 2-(trifluoromethyl)chromones with active methylene
compounds in the presence of sodium ethoxide affords two types
of products: 6-(2-hydroxyaryl)-3-cyano-4-(trifluoromethyl)-2-
pyridones with cyanoacetamides and 7-hydroxy-9-(trifluoro-
methyl)-6H-benzo[c]chromen-6-ones with ethyl cyanoacetate
and diethyl malonate. The latter reaction is a straightforward and
convenient route to functionalized benzo[c]coumarins and has
advantages with regard to ease of operation and the ready avail-
ability of starting materials.
Acknowledgment
This work was supported financially by the Russian Foundation
for Basic Research (Grant 11-03-00126).
References and notes
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CO2Et
O
O
X
EtO2C
X
X
O
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CF3
R
R
R
R
OH
OH
A
B
path a
CF3
X
O
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2 XCH2CO2Et
EtONa
CF3
OH
O
O
Y
5
8 (X = CN, Y = NH),
9 (X = CO2Et, Y = O)
path b
OEt
O
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Scheme 3. Possible mechanism for the formation of products 8 and 9.

6274
V. Ya. Sosnovskikh et al. / Tetrahedron Letters 52 (2011) 6271–6274
21. Krishnaiah, A.; Narsaiah, B. J. Fluorine Chem. 2002, 113, 133–137.
(ATR) 3403, 3294, 2222, 1696, 1610, 1598, 1548, 1519, 1478 cmꢀ1 1H NMR
;
22. 6-(2-Hydroxyphenyl)-1-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-
carbonitrile (7b). Yield 74%, light brown crystals, mp 221–222 °C (EtOH); IR
(400 MHz, DMSO-d6) d 3.88 (s, 3H, MeO), 6.99 (dd, 1H, H-2, J = 9.0, 2.5 Hz), 7.01
(d, 1H, H-4, J = 2.5 Hz), 7.73 (s, 1H, H-10), 8.10 (br s, 2H, NH, OH), 8.35 (d, 1H,
H-1, J = 9.0 Hz); 19F NMR (376 MHz, DMSO-d6) d ꢀ63.2 (s, CF3); 13C NMR
(ATR) 3151, 2232, 1634, 1601, 1571, 1557 cmꢀ1 1H NMR (400 MHz, DMSO-d6)
;
3
d 3.38 (s, 3H, Me), 6.67 (s, 1H, H-5), 6.99 (t, 1H, H-50, J = 7.5 Hz), 7.02 (d, 1H, H-
30, J = 8.3 Hz), 7.32 (dd, 1H, H-60, J = 7.5, 1.6 Hz), 7.43 (ddd, 1H, H-40, J = 8.3, 7.5,
1.6 Hz), 10.48 (s, 1H, OH); 19F NMR (376 MHz, DMSO-d6) d ꢀ64.6 (s, CF3); 13C
NMR (100 MHz, DMSO-d6) d 34.8 (Me), 97.0 (q, C-3, 3JC,F = 2.2 Hz), 103.8 (q, C-5,
3JC,F = 4.4 Hz), 113.4 (CN), 116.0 (C-30), 119.7 (C-50), 120.7 (C-10), 121.1 (q, CF3,
(100 MHz, DMSO-d6) d 56.1 (MeO), 88.3 (q, C-8, JC,F = 1.5 Hz), 101.0 (C-4),
3
104.9 (C-6a), 106.1 (q, C-10, JC,F = 5.1 Hz), 109.6 (C-10b), 113.2 (C-2), 114.1
1
2
(CN), 122.2 (q, CF3, JC,F = 275.0 Hz), 126.8 (C-1), 136.6 (q, C-9, JC,F = 31.5 Hz),
141.4 (C-10a), 153.2 (C-4a), 154.8 (C-7), 160.8 (C-6), 163.2 (C-3). Anal. Calcd for
C
16H9F3N2O3: C, 57.49; H, 2.71; N, 8.38. Found: C, 57.33; H, 2.64; N, 8.33.
2
1JC,F = 275.8 Hz), 129.8 (C-60), 132.5 (C-40), 143.9 (q, C-4, JC,F = 33.0 Hz), 154.3
24. Ethyl 7-hydroxy-6-oxo-9-(trifluoromethyl)-6H-benzo[c]chromene-8-carboxylate
(9a). Yield 62%, colorless crystals, mp 139–140 °C (EtOH); IR (ATR) 1737,
(C-20), 156.7 (C-6), 160.1 (C-2). Anal. Calcd for C14H9F3N2O2: C, 57.15; H, 3.08;
N, 9.52. Found: C, 57.02; H, 3.43; N, 9.50.
1682, 1627, 1608, 1562 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d 1.36 (t, 3H, Me,
;
23. 7-Hydroxy-6-imino-9-(trifluoromethyl)-6H-benzo[c]chromene-8-carbonitrile
J = 7.0 Hz), 4.38 (q, 2H, CH2O, J = 7.0 Hz), 7.48 (ddd, 1H, H-2, J = 8.3, 7.3, 1.0 Hz),
7.48 (dd, 1H, H-4, J = 8.3, 1.0 Hz), 7.67 (ddd, 1H, H-3, J = 8.3, 7.3, 1.3 Hz), 8.17 (s,
1H, H-10), 8.47 (dd, 1H, H-1, J = 8.3, 1.3 Hz), 11.76 (s, 1H, OH); 19F NMR
(376 MHz, DMSO-d6) d ꢀ60.0 (s, CF3); 13C NMR (100 MHz, DMSO-d6) d 14.2
(8a). Yield 66%, yellow crystals, mp 303–305 °C (DMF); IR (ATR) 3403, 3296,
.
2225, 1695, 1620, 1601, 1591 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6) d 7.41 (d,
1H, H-4, J = 8.0 Hz), 7.43 (t, 1H, H-2, J = 7.6 Hz), 7.67 (td, 1H, H-3, J = 7.8,
1.3 Hz), 7.78 (s, 1H, H-10), 8.02–8.32 (br s, 1.7H, NH, OH), 8.16 (s, 0.3H, NH),
8.38 (d, 1H, H-1, J = 8.0 Hz); 19F NMR (376 MHz, DMSO-d6) d ꢀ63.1 (s, CF3).
Anal. Calcd for C15H7F3N2O2: C, 59.22; H, 2.32; N, 9.21. Found: C, 59.62; H, 2.51;
N, 9.43.
3
(Me), 62.5 (CH2), 110.1 (C-6a), 110.7 (q, C-10, JC,F = 4.4 Hz), 117.2 (C-10b),
3
1
117.8 (C-4), 119.7 (q, C-8, JC,F = 2.2 Hz), 123.0 (q, CF3, JC,F = 275.1 Hz), 125.3
2
(C-1), 126.0 (C-2), 132.8 (C-3), 132.9 (q, C-9, JC,F = 32.3 Hz), 137.3 (C-10a),
151.0 (C-4a), 158.7 (C-6), 164.1 (C-7), 164.3 (C@O). Anal. Calcd for
7-Hydroxy-6-imino-3-methoxy-9-(trifluoromethyl)-6H-benzo[c]chromene-8-
carbonitrile (8c). Yield 42%, light brown crystals, mp 259–260 °C (DMF); IR
C
17H11F3O5ꢁ0.5H2O: C, 56.52; H, 3.35. Found: C, 56.69; H, 3.22.
25. Darbarwar, M.; Sundaramurthy, V. Synthesis 1982, 337–388.