1,3,4,6-tetracarbonyl compounds: VI. Synthesis of 2-substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic acid esters and amides

Article abstract of DOI:10.1023/A:1013839632482

The Knoevenagel reaction of 5-aryl-2,3-dihydrofuran-2,3-diones with ethyl cyanoacetate or malonodinitrile yields 2-substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic acid esters or amides which exhibit biological activity. The structure of the product

Full text of DOI:10.1023/A:1013839632482

Russian Journal of Organic Chemistry, Vol. 37, No. 11, 2001, pp. 1528 1533. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 11, 2001,
pp. 1604 1609.
Original Russian Text Copyright
2001 by Koz’minykh, Igidov, Kasatkina.
1,3,4,6-Tetracarbonyl Compounds: VI.* Synthesis
of 2-Substituted 6-Aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic
Acid Esters and Amides
V. O. Koz’minykh, N. M. Igidov, and Yu. S. Kasatkina
Perm State Pharmaceutical Academy, P.O. Box 8519, Perm, 614051 Russia
e-mail: kvo@pi.ccl.ru
Received February 1, 2001
Abstract The Knoevenagel reaction of 5-aryl-2,3-dihydrofuran-2,3-diones with ethyl cyanoacetate or
malonodinitrile yields 2-substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic acid esters or amides
which exhibit biological activity. The structure of the products is discussed, taking into account the structure
of known 3,4-dihydroxy-6-oxo-2,4-hexadienoic acid esters and 1,6-diaryl-3,4-dihydroxy-2,4-hexadiene-
1,6-diones.
Claisen condensation of aryl methyl ketones with
diethyl oxalate in the presence of sodium methoxide
or ethoxide provides a convenient preparative method
of synthesis of 1,6-diaryl-3,4-dihydroxy-2,4-hexadi-
ene-1,6-diones (1,6-diarylhexane-1,3,4,6-tetraones) I
[2 5]. Compounds I usually exist in solution as
equilibrium mixtures of two tautomers: open-chain
ketoenol form A and ring isomer B [5 7] (Scheme 1).
As concerns such 1,3,4,6-tetracarbonyl compounds as
3,4,6-trioxocarboxylic acid derivatives, 6-aryl-3,4-di-
hydroxy-6-oxo-2,4-hexadienoic acid esters II have
been reported [8 12]. Esters II exist in solution as
two open-chain tautomers C and D and ring semi-
acetal tatoumer E, the latter prevailing. These com-
pounds are formed by addition of water at the exo-
cyclic double bond of 5-aryl-3-oxo-2,3-dihydro-2-
furylideneacetic acid esters III [8, 9]. Another route to
oxo esters II is based on the reaction of 5-aryl-2,3-di-
hydrofuran-2,3-diones IV with ketene acetals [10 12]
(Scheme 1).
We previously reported that 5-aryl-2,3-dihydro-
furan-2,3-diones IV readily react with aryl methyl
ketones under mild conditions in the presence of
bases, yielding tetraoxo derivatives I [5, 7, 13, 14]
(Scheme 1). We also found that oxo lactones IV are
capable of reacting (according to Knoevenagel) with
other carbonyl compounds having an active methylene
group to afford various 1,3,4,6-tetracarbonyl com-
pounds and their biologically active analogs [14 17].
The present communication reports on the results of
our study of the reactions of compounds IVa IVe
with ethyl cyanoacetate and malonodinitrile in the
presence of triethylamine as catalyst with the goal of
obtaining 1,3,4,6-tetracarbonyl systems. The reactions
were carried out in dioxane at room temperature, and
2-substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadi-
enoic acid esters or amides Va Vj were obtained in
satisfactory yields (Scheme 2, Tables 1 3). In some
cases, a small amount (2 5%) of the corresponding
tetraketone I was also isolated.
The spectral parameters of 2,4-hexadienoic acid
derivatives V are consistent with their structure and
with the known data for structurally related 3,4-di-
hydroxy-1,6-diphenyl-2,4-hexadiene-1,6-dione (I,
Ar = Ph) [5] and methyl 6-phenyl-3,4-dihydroxy-6-
oxo-2,4-hexadienoate (II, Alk = Me, Ar = Ph)
[8, 9, 11] which were selected as model compounds
(Tables 2, 3).
Prior to our studies, no alternative methods for
introduction of an ester group in the synthesis of
1,3,4,6-tetracarbonyl compounds have been known.
Such factors as poor yields of the products and limited
number of available starting compounds (e.g., reagents
like III) strongly restrict possible applications of the
above reactions to preparation of a wide series of
polycarbonyl systems having an ester or amide group.
____________
The IR spectra of products V (Table 2) contained
absorption bands due to stretching vibrations of the
1
*
For communication V, see [1].
amide group (3375 3195 and 1710 1660 cm ), ester
1070-4280/01/3711-1528$25.00 2001 MAIK Nauka/Interperiodica

1,3,4,6-TETRACARBONYL COMPOUNDS: VI.
1529
Scheme 1.
Scheme 2.
IVa, Va, Vf, R = H; IVb, Vb, Vg, R = Me; IVc, Vc, Vh, R = Br; IVd, Vd, Vi, R = Cl; IVe, Ve, Vj, R = F; Va Ve,
X = CO2Et; Vf Vj, X = CN.
1
carbonyl (1718 1703 cm ; compounds Va Ve), and
Vb in boiling methanol containing hydrochloric acid
1
we obtained ethyl 6-aryl-2-carbamoyl-4-hydroxy-3-
methoxy-6-oxo-2,4-hexadienoates VIa and VIb in
preparative yields (Scheme 3, Tables 1 3). As ex-
pected, enol ethers VI, unlike initial enols V, give
a negative color test with a 10% solution of iron(III)
chloride in ethanol.
cyano group (2229 2208 cm ; Vf Vj). Also, a broad
low-frequency band was observed in the region 1665
1580 cm . This band corresponds to C O stretching
vibrations of the -dicarbonyl fragment which has
a six-membered H-chelate structure due to intramole-
cular hydrogen bond like OH O C [5, 18]. An ana-
1
1
logous band at 1612 1568 cm was observed in the
In the IR spectrum of crystalline compound VIa
IR spectra of 1,3,4,6-tetraketones I [5]. The presence
of an enol hydroxy group was proved by the color
test: a characteristic cherry-red color appeared on
treatment of compounds V with a 10% solution of
iron(III) chloride in ethanol.
We failed to reveal the hydroxy group of the keto-
enol moiety (C3OH) of compounds V by spectral
methods, but it gives rise to the corresponding methyl
ether on treatment with methanol in the presence of
hydrochloric acid. By heating of compounds Va and
(Table 2) we observed a broad absorption band at
1665 1637 cm due to stretching vibrations of the
1
-dicarbonyl fragment; its position suggests formation
of H-chelate ring. The position of bands from the ester
and amide groups changes insignificantly, as com-
pared with the corresponding bands of Va.
1
The 5-H signal in the H NMR spectra of esters
and amides V in DMSO-d6 (Table 3) appears at
6.75 6.92 ppm, which is consistent with the data
for model 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 11 2001

1530
KOZ’MINYKH et al.
Scheme 3.
VI, R = H (a), Me (b).
acid esters II ( 6.81 6.95 ppm). The corresponding
signal (2-H or 5-H) in the spectra of 1,3,4,6-tetra-
ketones A is observed in a weaker field, at 7.05
from the C5H2 group appears at
3.66 (VIa) and
3.58 ppm (VIb), which corresponds to the -dicar-
bonyl tautomer. We can conclude that crystalline
compounds VI exist as keto enol tautomers and that
in DMSO solution -diketone form prevails. Factors
responsible for stabilization of different tautomeric
forms in crystal and in solution are now not clear.
It should be noted that addition of trifluoroacetic acid
to solutions of V and VI in DMSO-d6 almost does
7.24 ppm (
0.3 ppm) [5], owing to the deshielding
effect of the second benzene ring. The relatively
downfield position of signal from the CH proton of
the enolized aroylacetyl moiety in V conforms to the
known data for structurally related acylpyruvic acids
and their esters, amides, and other derivatives [16 20].
The lack of signals from CH2 and another CH groups
indicates the absence of tautomeric forms having the
structure of 2-substituted 6-aryl-3-hydroxy-4,6-dioxo-
2-hexenamides and (5-aryl-2-hydroxy-3-oxo-2,3-di-
hydro-2-furyl)acetamides.
1
not change the position of proton signals in the H
NMR spectra.
As might be expected, the main fragmentation
pathway of esters and amides V and VI, as well as
of model compounds I (Ar = Ph) [21] and II (Alk =
Me, Ar = Ph), under electron impact is elimination of
the aroylacetyl fragment (ion F, m/z 146 and 147)
and aroyl and phenyl ions (G and H, Scheme 4). The
1
On the other hand, the H NMR spectra of keto
esters VI differ from the spectra of initial compounds
V: the former display no C5H signal. Instead, a singlet
Table 1. Yields, melting points, and elemental analyses of 2,3-disubstituted 6-aryl-4-hydroxy-6-oxo-2,4-hexadienoic
acid esters and amides Va Vj, VIa, and VIb
Found, %
H
Calculated, %
Comp.
no.
Yield, %
mp,a
C
Formula
C
N (Hlg)
C
H
N (Hlg)
Va
Vb
Vc
92
53
59
223 224
220 221
225 226
59.29
60.53
47.22
5.12
5.10
3.80
4.37
4.58
3.87
C15H15NO6
C16H17NO6
C15H14BrNO6
59.01
60.18
46.90
4.95
5.37
3.67
4.59
4.39
3.65
(20.51)
4.41
(20.80)
4.12
Vd
49
227 228
52.84
4.38
C15H14SlNO6
53.03
4.15
(10.02)
4.16
10.57
9.90
(10.43)
4.33
10.85
10.29
8.31
Ve
Vf
Vg
Vh
32
71
68
82
212 213
234 235
233 234
274 275
55.45
60.65
61.53
46.57
4.49
4.13
4.67
3.07
C15H14FNO6
C13H10N2O4
C14H12N2O4
C13H9BrN2O4
55.73
60.47
61.76
46.31
4.37
3.90
4.44
2.69
8.62
(23.49)
9.34
(23.70)
9.57
Vi
61
261 262
53.64
3.26
C13H9ClN2O4
53.35
3.10
(11.83)
9.87
4.56
(12.11)
10.14
4.39
Vj
VIa
VIb
52
90
61
253 254
211 212
215 216
56.70
60.47
60.92
3.45
5.71
6.03
C13H9FN2O4
C16H17NO6
C17H19NO6
56.53
60.18
61.25
3.28
5.37
5.75
4.34
4.20
a
With decomposition.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 11 2001

1,3,4,6-TETRACARBONYL COMPOUNDS: VI.
1531
Table 2. IR spectra of model compounds I and II and esters and amides V and VI
Comp.
no.
1
IR spectrum, , cm
Ia
1605 1585 (CO, chelat.) [5]
IIb
Va
Vb
Vc
Vd
Ve
Vg
Vi
3085 3070 (OH), 1712 (CO2Me), 1665 (CO), 1590 1580, 1555
3332 (CONH2), 1718 (CO2Et), 1672 (CONH2), 1640 1620, 1596 (CO, chelat.)
3323 (CONH2), 1710 (CO2Et), 1672 (CONH2), 1635 1620, 1605 (CO, chelat.)
3330 (CONH2), 1712 (CO2Et), 1670 (CONH2), 1645 1630, 1580 (CO, chelat.)
3375 (CONH2), 1703 (CO2Et), 1660 (CONH2), 1638, 1622, 1585 (CO, chelat.)
3340 (CONH2), 1707 (CO2Et), 1690 (CONH2, C C), 1650 1620 (CO, chelat.)
3240 3225 (CONH2), 2208 (C N), 1706, 1680 (CONH2, C C), 1652, 1625, 1602, 1585 (CO, chelat.)
3225 3195 (CONH2), 2229 (C N), 1710 (C C, CONH2), 1656, 1587 (CO, chelat.)
3360 3345 (CONH2), 3145 3130 (CH), 2229 (C N), 1719, 1701 (C C, CONH2), 1665 1635, 1593 (CO,
chelat.)
Vj
VIa
3460 (CONH2), 1722 (CO2Et), 1704 (CONH2, C C), 1665 1637 (CO, chelat.)
a
b
Ar = Ph.
Alk = Me, Ar = Ph.
Table 3. 1H NMR spectra of model compounds I and II and esters and amides V and VI in DMSO-d6
Comp.
no.
Chemical shifts , ppm
Ia, b
3.48 d and 3.95 d (2H, CH2, J = 14.0 Hz, B, 53%), 6.35 s (1H, 4-H, B), 7.15 8.05 m (12H, 2-H, 5-H, A;
2C6H5, A and B), 7.07 s (2H, 2-H, 5-H, A, 100%), 7.25 8.08 m (10H, 2C6H5), 15.27 br.s (2H, OH) [5]
2.76 d and 2.88 d (2H, CH2, J = 15.0 Hz, E, 49%) (2.70 d and 3.05 d; E, 68% [11]), 3.66 s (3H, CO2Me, D,
35%) (9% of D [11]), 3.69 s (3H, CO2Me, E), 3.78 s (3H, CO2Me, C, 16%) (22% of C [11]), 3.89 s (2H,
CH2, D), 5.95 s (1H, 4-H, E), 6.82 s (1H, 5-H, C, D), 7.12 s (1H, 2-H, C), 7.33 7.75 m (1H, 2-OH, E;
5H, C6H5, C E)
IIb, c
Va
Vb
Vc
Vd
Ve
1.22 t (3H, CH2Me); 4.18 q (2H, CH2Me); 6.83 s (1H, 5-H); 7.55 m, 7.67 m, and 7.98 m (5H, C6H5); 8.83 s
and 10.08 s (2H, NH2)
1.24 t (3H, CH2Me), 2.42 s (3H, Me), 4.20 q (2H, CH2Me), 6.80 s (1H, 5-H), 7.36 d and 7.90 d (4H, C6H4),
8.84 s and 10.09 s (2H, NH2)
1.22 t (3H, CH2Me), 4.15 q (2H, CH2Me), 6.75 s (1H, 5-H), 7.62 d and 7.90 d (4H, C6H4), 8.87 s and
10.05 s (2H, NH2)
1.28 t (3H, CH2Me), 4.20 q (2H, CH2Me), 6.80 s (1H, 5-H), 7.53 d and 8.02 d (4H, C6H4), 8.82 s and
10.15 s (2H, NH2)
1.25 t (3H, CH2Me), 4.21 q (2H, CH2Me), 6.79 s (1H, 5-H), 7.32 m and 8.07 m (4H, C6H4), 8.75 s and
10.04 s (2H, NH2)
Vf
6.90 s (1H, 5-H); 7.55 m, 7.67 m, and 8.00 m (5H, C6H5); 10.18 s (2H, 2NH2)
2.72 s (3H, Me), 6.92 s (1H, 5-H), 7.35 d and 7.90 d (4H, C6H4), 10.33 s (2H, NH2)
6.88 s (1H, 5-H), 7.64 8.00 m (4H, C6H4), 10.28 s (2H, NH2)
6.89 s (1H, 5-H), 7.57, 8.02 m (4H, C6H4), 10.19 s (2H, NH2)
6.88 s (1H, 5-H), 7.33, 8.09 m (4H, C6H4), 10.14 s (2H, NH2)
1.21 t (3H, CH2Me), 3.15 s (3H, OMe), 3.66 s (2H, CH2), 4.15 q (2H, CH2Me), 7.42 8.02 m (5H, C6H5),
8.51 s and 9.45 s (2H, NH2)
Vg
Vh
Vi
Vj
VIa
VIb
1.25 t (3H, CH2Me), 2.36 s (3H, Me), 3.16 s (3H, OMe), 3.49 d and 3.64 d (2H, CH2), 4.15 q (2H, CH2Me),
7.28 d and 7.81 d (4H, C6H4), 8.32 s and 9.34 s (2H, NH2)
a
b
c
Ar = Ph.
In CDCl3. Alk = Me, Ar = Ph.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 11 2001

1532
KOZ’MINYKH et al.
molecular ion peaks in the mass spectra of I, II, and
VI have low intensity, Compounds V give no mole-
cular ion peaks, but they readily lose water with
formation of [M H2O]+ ions ( 18). A similar pattern
is typical of tetraketones I [21].
condensation of acetophenone with diethyl oxalate in
the presence of MeONa [2, 4]. Methyl 3,4-dihydroxy-
6-oxo-6-phenyl-2,4-hexadienoate (II, Alk = Me,
Ar = Ph) was synthesized as described in [8, 9].
2-Substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-
hexadienoic acid esters and amides Va Vi (general
procedure). To a solution of 10 mmol of 5-aryl-2,3-
dihydrofuran-2,3-dione IVa IVe in 40 50 ml of
dioxane we added 10 mmol of ethyl cyanoacetate or
malonodinitrile and 0.4 ml of triethylamine. After
24 h, the precipitate was filtered off, washed with
ethanol, and recrystallized from dimethylformamide.
Compounds Va Vj were isolated as light yellow
substances poorly soluble in most organic solvents.
Scheme 4.
Ethyl 6-aryl-2-carbamoyl-4-hydroxy-3-methoxy-
6-oxo-2,4-hexadienoates VIa and VIb. A mixture of
5 mmol of compound Va or Vb, 100 ml of methanol,
and 6 ml of hydrochloric acid was refluxed for 1 h.
The precipitate was filtered off and recrystallized from
methanol. Products VIa and VIb were isolated as
colorless crystalline substances.
Thus, 5-aryl-2,3-dihydrofuran-2,3-diones IV readily
react with ethyl cyanoacetate and malonodinitrile in
the presence of triethylamine, affording addition prod-
ucts at the lactone carbonyl group of the heteroring.
The resulting semiacetals undergo ring opening at
the C2 O bond, and mild hydrolysis of the cyano
group (in the presence of water) leads to formation of
compounds V. Nucleophilic addition of CH acids at
the lactone carbonyl group of furandiones IV is not
surprising: analogous examples have been well known
and described in detail [5, 7, 12, 14 17, 22, 23].
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