Synthesis and Structure (Z)-N-Aryl-2-hydroxy-4-oxo-4-phenylbut-2-enamides
RUSSIAN JOURNAL OF GENERAL CHEMISTRY
Synthesis and Structure (Z)-N-Aryl-2-hydroxy-4-oxo-4-phenylbut-2-enamides
V. L. Gein 1
T. M. Zamaraeva 1
E. V. Gorgopina 1
N. M. Igidov 1
O. V. Bobrovskaya 1
M. V. Dmitriev 0
0 Perm State National Research University , Perm , Russia
1 Perm State Pharmaceutical Academy , ul. Polevaya 2, Perm, 614990 Russia
-Reactions of 5-phenyl-2,3-dihydrofuran-2,3-dione with aromatic amines in anhydrous dioxane or methyl benzoylpyruvate with aromatic amines in the presence of sodium acetate in glacial acetic acid afforded (Z)-N-aryl-2-hydroxy-4-oxo-4-phenylbut-2-enamides. Aroylpyruvic acid amides are of obvious chemical interest. These polyfunctional reagents show high reactivity due to the presence of several reaction sites in their structure [1, 2]. They can act as C-nucleophiles and carbonyl electrophiles in the reactions, being promising starting materials for the synthesis of a variety of acyclic and heterocyclic compounds [1-4]. R = С6H5 (1), 4-BrС6H4 (2), 4-IС6H4 (3), 3-ClС6H4 (4), 4-C2H5OOCС6H4 (5), 4-CH3С6H4 (6), 4-CH3OС6H4 (7), 4-NH2SO2С6H4CH2CH2 (8).
methyl benzoylpyruvate; 5-phenyl-2; 3-dihydrofuran-2; 3-dione; arylamines; aroylpyruvic acid amides
The most studied method for the preparation of
N-substituted amides of aroylpyruvic acids is the ring
opening of 5-aryl-2,3-dihydrofuran-2,3-diones under
the action of N-nucleophiles in an inert solvent
medium with an equimolar ratio of the reagents [5, 6].
Because of a number of drawbacks in this method ,
it remains urgent to find optimal conditions for the
synthesis of amides of aroylpyruvic acids, which due
to widely varying pharmacophore groups in their
structure can be used further in the preparation of
previously unknown and inaccessible functional
A new simple method for the preparation of
Narylamides of aroylpyruvic acids reported in 
includes the reaction of arylamines with methyl
aroylpyruvates in acetic acid in the presence of
anhydrous sodium acetate. Later, arylamides obtained
have been modified with
4-aminobenzenesulfonylacetamide sodium (sodium sulfacetamide) ,
4-aminobenzenesulfonylguanidine (sulgine) , streptocide,
and norsulfazole fragments .
Continuing research in this direction, we apply this
method for the synthesis of new N-arylamides of
aroylpyruvic acids and studied their spatial structure.
For the comparative study,
(Z)-N-aryl-2-hydroxy-4oxo-4-phenylbut-2-enamides were prepared by reacting
5-phenyl-2,3-dihydrofuran-2,3-dione with anilines in an
To establish the possibility of using alkylamines in
the synthesis of aroylpyruvic acid amides, we
performed the reaction with 4-(2-aminoethyl)
benzenesulfonamide by two aforementioned methods.
However, we did not succeed in obtaining compound 8
according to method b.
Compounds 1–8 are yellow crystalline substances
soluble in DMF, DMSO, soluble at heating in acetic
acid, ethanol, and insoluble in water (Scheme 1).
In the 1H NMR spectra of compounds 1–8, there
were singlets of COCH2CO (4.53–4.64 ppm), CH=
(7.02–7.17 ppm), CONH groups (8.99–10.78 pm), as
well as the signals of aromatic fragments. In the
spectrum of 8, the protons of both CH2 and NH2
groups were recorded in the regions of 2.86–3.51 and
7.32 ppm, respectively.
Crystal structure of compound 5 was studied by
single-crystal X-ray diffraction method (see the
figure). The crystals were obtained by slow
crystallization from acetic acid. The molecule of 5
crystallizes in the centrosymmetric spatial group of the
monoclinic crystal system. The molecule is practically
planar. The electron density of the keto-enol fragment
is strongly delocalized, which is expressed in
equalizing the lengths of multiple and single C–C and
C–O bonds (see Table). The position of the hydrogen
atom of the enol hydroxy group was refined taking into
account the disordering due to the existence of
tautomeric equilibrium [the ratio of the populations of
the H4 and H5 atoms is 0.59(
) to 0.41(
respectively]. In addition to the intramolecular hydrogen
bond in the keto-enol fragment the molecule also has
an intramolecular hydrogen bond of non-classical type
С6–H6···O3 [H6···O3 2.329, С6···O3 2.927(
) Å]. The
crystal packing is stabilized by van der Waals
interactions and several shortened С–H···O contacts.
According to the studies performed, the most
effective and convenient method for the synthesis of
containing arylamine fragment with an
electronwithdrawing group is the reaction of benzoylpyruvic
acid methyl ester with arylamines in glacial acetic acid
General view of the molecule of compound 5 in the crystal
represented by thermal ellipsoids with 50% probability.
in the presence of anhydrous sodium acetate. When
using an aromatic amine with an electron-donor
substituent or an alkylamine for the preparation of
benzoylpyruvic acid amides, it is more expedient to use the
ring opening reaction of 5-aryl-2,3-dihydrofuran-2,3-dione
). a. To 1.0 g (0.0057 mol) of
5-phenyl-2,3-dihydrofuran-2,3-dione in 20 mL of anhydrous dioxane was
added 0.52 mL (0.0057 mol) of aniline in 2 mL of
anhydrous dioxane. Then the solvent was distilled off,
the precipitate was washed with ethyl alcohol.
b. A mixture of 8.24 g (0.04 mol) of methyl
benzoylpyruvate and 3.28 g (0.04 mol) of anhydrous
sodium acetate in 10 mL of glacial acetic acid was
added to 3.65 mL (0.04 mol) of aniline dissolved in
glacial acetic acid. The reaction mixture was refluxed
for 20–30 min. The residue was filtered off and
recrystallized from acetic acid. Yield 1.09 g (72%,
method a), 6.74 g (63%, method b), mp 90–92°C. 1Н
NMR spectrum (DMSO-d6), δ, ppm: 4.63 s (2Н,
COCH2CO), 7.02 s (1Н, СН=), 7.12 t (1H, ArH, J =
7.5 Hz), 7.35 t (2H, ArH, J = 7.5 Hz), 7.52 t (1H, ArH,
J = 6.9 Hz), 7.59 t (2H, ArH, J = 6.9 Hz), 7.79 d (2H,
ArH, J = 7.5 Hz), 7.98 d (2H, ArH, J = 6.9 Hz), 10.37
s (1Н, СONH). Found, %: С 70.98, 72.02; Н 4.82,
4.99; N 5.12, 5.37. C16H13NO3. Calculated, %: С
71.90; Н 4.90; N 5.24.
). Yield 1.55 g (77%, method a),
5.95 g (86%, method b), mp 148–150°C. 1Н NMR
Some bond lengths in the molecule of 5
spectrum (DMSO-d6), δ, ppm: 4.62 s (2Н, COCH2CO),
7.17 s (1Н, СН=), 7.56 d (1H, ArH, J = 8.7 Hz), 7.61 d
(1H, ArH, J = 8.7 Hz), 7.68 t (3H, ArH, J = 7.2 Hz),
7.76 d (1H, ArH, J = 8.7 Hz), 7.81 d (1H, ArH, J =
8.7 Hz), 7.99 d (1H, ArH, J = 7.2 Hz), 8.06 d (1H,
ArH, J = 7.5 Hz), 10.59 s (1Н, СONH). Found, %: С
55.39, 55.62; Н 3.39, 3.58; N 3.92, 4.17. C16H12BrNO3.
Calculated, %: С 55.51; Н 3.49; N 4.05.
). Yield 1.85 g (83%, method a),
7.3 g (93%, method b), mp 134–136°C. 1Н NMR
spectrum (DMSO-d6), δ, ppm: 4.61 s (2Н, COCH2CO),
7.16 s (1Н, СН=), 7.55–8.06 m (9H, ArH), 10.55 s
(1Н, СONH). Found, %: С 48.77, 49.01; Н 2.98, 3.17;
N 3.44, 3.67. C16H12INO3. Calculated, %: С 48.88; Н
3.08; N 3.56.
). Yield 4.5 g (75%, method b), mp
242–244°C. 1Н NMR spectrum (DMSO-d6), δ, ppm:
4.63 s (2Н, COCH2CO), 7.15 s (1Н, СН=), 7.18–8.05
m (9H, ArH), 10.62 s (1Н, СONH). Found, %: С
63.59, 63.81; Н 3.94, 4.10; N 4.51, 4.75. C16H12ClNO3.
Calculated, %: С 63.69; Н 4.01; N 4.64.
). Yield 10.95 g (81%, method b),
mp 127–129°C (EtOH). 1Н NMR spectrum
(DMSOd6), δ, ppm: 1.36 t (3Н, СH3CH2O, J = 6.9 Hz), 4.32 q
(2Н, СH3CH2O, J = 6.9 Hz), 4.64 s (2Н, COCH2CO),
7.16 s (1Н, СН=), 7.55–8.03 m (9H, ArH), 10.78 s
(1Н, СONH). Found, %: С 67.16, 67.38; Н 4.95, 5.14;
N 4.01, 4.24. C19H17NO5. Calculated, %: С 67.25; Н
5.05; N 4.13.
). Yield 0.8 g (50%, method a), mp
92–94°C (EtOH). 1Н NMR spectrum (DMSO-d6), δ,
ppm: 2.29 s (3Н, CH3C6H4), 4.61 s (2Н, COCH2CO),
7.16 s (1Н, СН=), 7.12–8.06 m (9H, ArH), 10.34 s (1Н,
СONH). Found, %: С 72.47, 72.69; Н 5.28, 5.45; N
4.86, 5.11. C17H15NO3. Calculated, %: С 72.58; Н 5.37;
). Yield 1.25 g (74%, method
a), mp 110–112°C (EtOH). 1Н NMR spectrum
(DMSOd6), δ, ppm: 3.76 s (3Н, CH3OC6H4), 4.60 s (2Н,
COCH2CO), 7.17 s (1Н, СН=), 6.92–8.03 m (9H,
ArH), 10.33 s (1Н, СONH). Found, %: С 68.56, 68.80;
Н 4.98, 5.19; N 4.59, 4.84. C17H15NO4. Calculated, %:
С 68.68; Н 5.09; N 4.71.
). Yield 1.75 g (82%,
method a), mp 165–167°C (EtOH). 1Н NMR spectrum
(DMSO-d6), δ, ppm: 2.86 m (2H, C2H2), 2.95 m (1H,
C1HB), 3.51 m (1H, C1HA), 4.53 s (2H, COCH2CO),
7.08 s (1H, CH=), 7.32 s (1H, SO2NH2), 7.38–8.05 m
(9H, ArH), 8.99 s (1Н, СONH). Found, %: С 57.63; Н
4.80; N 7.55; S 8.65. С18H18N2O5S. Calculated, %: С
57.74; Н 4.85; N 7.48; S 8.56.
1H NMR spectra (DMSO-d6) were registered on a
Bruker 500 spectrometer (500.13 MHz), internal
reference TMS. Elemental analysis was performed
using a Perkin Elmer 2400 analyzer. Melting points
were determined on a Melting Point M-565 apparatus.
X-Ray diffraction analysis was performed on a
Xcalibur Ruby diffractometer equipped with a CCD
detector using the standard procedure [MoKα-radiation,
) K, ω-scanning in 1° increments] . Empirical
correction for absorption was performed using the
SCALE3 ABSPACK algorithm . The crystals
are monoclinic, space group P21/c, a 12.779(
5.4942(17), c 24.676(
) Å, β 97.54(
)°, V 1717.5(
Z 4. The structure was solved by the direct method
using SHELX software  and refined by the
fullmatrix least squares method with respect to F2 in
anisotropic approximation for all non-hydrogen atoms
using SHELXL  and OLEX2 programs . The
positions of hydrogen atoms of the NH and OH groups
were refined independently in isotropic approximation,
and other atoms were refined using a rider model. For
O–H bond lengths, the values of 0.82 Å were
determined by the soft DFIX constraint. The final
refinement parameters are as follows: R1 0.0659, wR2
0.1711 [for 1558 reflections with I > 2σ(I)], R1 0.1781,
wR2 0.2402 (for all 4031 independent reflections),
S 1.019. The X-ray diffraction data were deposited at
the Cambridge Crystallographic Data Centre (CCDC
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