Reaction of Acylpyruvic Acids and Their Esters with N-(2-Aminophenyl)acetamide

Article abstract of DOI:10.1134/S1070428019030254

Acylpyruvic acids and their esters regioselectively reacted with N-(2-aminophenyl)acetamide to give acyclic enamines, substituted (Z)-2-[(2-acetamidophenyl)amino]-4-oxobut-2-enoates, whose structure was confirmed by X-ray analysis. These compounds were formed as a result of condensation involving the primary amino group of N-(2-aminophenyl)acetamide at the most electrophilic C²=O carbonyl group of acylpyruvic acid or its ester. The obtained enamines underwent thermal heterocyclization to (Z)-3-(2-oxoethylidene)-3,4-dihydroquinoxalin-2(1H)-ones having no substituent on the N¹ atom rather than expected (Z)-1-acetyl-3-(2-oxoethylidene)-3,4-dihydroquinoxalin-2(1H)-ones. The heterocyclization involves intramolecular exchange between the amide and carboxylic acid (ester) fragments. The described transformations occur under mild conditions, require no catalyst or other additives, and therefore conform to the “green chemistry” principles. The products may be interesting from the viewpoints of medicinal chemistry, pharmacology, and fine organic synthesis.

Full text of DOI:10.1134/S1070428019030254

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 3, pp. 402–405. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 3, pp. 469–473.
SHORT
COMMUNICATIONS
Reaction of Acylpyruvic Acids and Their Esters
with N-(2-Aminophenyl)acetamide
E. E. Stepanovaa, M. V. Dmitrieva, and A. N. Maslivetsa*
a Perm State University, ul. Bukireva 15, Perm, 614990 Russia
*e-mail: koh2@psu.ru
Received September 19, 2018; revised October 25, 2018; accepted November 1, 2018
Abstract—Acylpyruvic acids and their esters regioselectively reacted with N-(2-aminophenyl)acetamide to
give acyclic enamines, substituted (Z)-2-[(2-acetamidophenyl)amino]-4-oxobut-2-enoates, whose structure was
confirmed by X-ray analysis. These compounds were formed as a result of condensation involving the primary
amino group of N-(2-aminophenyl)acetamide at the most electrophilic C2=O carbonyl group of acylpyruvic
acid or its ester. The obtained enamines underwent thermal heterocyclization to (Z)-3-(2-oxoethylidene)-
3,4-dihydroquinoxalin-2(1H)-ones having no substituent on the N1 atom rather than expected (Z)-1-acetyl-
3-(2-oxoethylidene)-3,4-dihydroquinoxalin-2(1H)-ones. The heterocyclization involves intramolecular
exchange between the amide and carboxylic acid (ester) fragments. The described transformations occur under
mild conditions, require no catalyst or other additives, and therefore conform to the “green chemistry”
principles. The products may be interesting from the viewpoints of medicinal chemistry, pharmacology, and
fine organic synthesis.
Keywords: acylpyruvic acids, enamines, X-ray analysis, quinoxaline, cyclization.
DOI: 10.1134/S1070428019030254
Reactions of acylpyruvic acids and their esters with
o-phenylenediamine and its derivatives were studied
with the goal of obtaining substituted (Z)-3-(2-oxo-
ethylidene)-3,4-dihydroquinoxalin-2(1H)-ones which
exhibit a pronounced biological activity, in particular
antioxidant [1], antimicrobial [2, 3], etc. In addition,
these compounds are important intermediate products
for the synthesis of various heterocyc systems [4–6].
The reactions with N-unsubstituted o-phenylenedi-
amine [1–4, 7–10] and N-phenyl-o-phenylenediamine
[3, 11–13] have been studied in most detail. There
are no published data on reactions of acylpyruvic acids
or their esters with N-(2-aminophenyl)acetamide
(N-acetyl-o-phenylenediamine).
from the corresponding reference values. The N1H1
hydrogen atom is involved in intramolecular hydrogen
bonds N1–H1···O1 and N1–H1···O4.
Enamines 2a–2c underwent thermal (140–170°C,
1–3 h; HPL monitoring) heterocyclization to 1-unsub-
stituted (Z)-3-(2-oxoethylidene)-3,4-dihydroquinoxa-
lin-2(1H)-ones 3a and 3b rather than to expected
(Z)-1-acetyl-3-(2-oxoethylidene)-3,4-dihydroquinoxa-
lin-2(1H)-ones A. Presumably, enamines 2a–2c are
formed via nucleophilic addition of the primary amino
group of N-(2-aminophenyl)acetamide to the C2=O
carbonyl carbon atom of 1a–1c, which is typical of
reactions of acylpyruvic acids and their esters with
aromatic amines [14]. Thermally initiated intramolec-
ular exchange between the amide and carboxylic acid
(ester) fragments of 2a–2c yields quinoxalinones 3a
and 3b.
(2Z)-2-(2-Acetamidoanilino)-4-oxo-4-phenylbut-
2-enoic acid (2a). A mixture of 1.00 g (5.2 mmol) of
compound 1a and 0.78 g (5.2 mmol) of N-(2-amino-
phenyl)acetamide in 10 mL of ethanol was refluxed for
1 h. The mixture was cooled and evaporated by half,
and the yellow solid was filtered off. Yield 1.20 g
Acylpyruvic acid derivatives 1a–1c reacted with
an equimolar amount of N-(2-aminophenyl)acetamide,
in boiling ethanol for 1–1.5 h (HPLC monitoring) to
give (Z)-2-(2-acetamidoanilino)-4-oxobut-2-enoates
2a–2c whose structure was confirmed by X-ray anal-
ysis of compound 2b (Fig. 1). Compound 2b crystal-
lized in a centrosymmetric space group belonging to
the orthorhombic crystal system. The bond lengths and
bond angles in molecule 2b did not differ appreciably
402

REACTION OF ACYLPYRUVIC ACIDS
403
H
N
O
N
H
–MeC(O)X
O
Me
NH
O
R
O
OH
NHAc
3a, 3b
∆
OX
+
O
NH
R
–H2O
O
Me
NH2
O
OX
R
N
O
O
1a–1c
2a–2c
N
H
–XOH
O
R
A
1, 2, R = Ph, X = H (a), R = Ph, X = Me (b), R = EtO, X = Et (c); 3, R = Ph (a), EtO (b).
(71%), mp 130–132°C (decomp., from EtOH). IR
spectrum, ν, cm–1: 3272 (NH, OH), 1715 (C=O).
1H NMR spectrum, δ, ppm: 2.11 s (3H, Me), 6.38 s
(1H, 3-H), 7.07 m (1H, Harom), 7.17 m (2H, Harom),
7.32 m (1H, Harom), 7.49–7.60 m (3H, Harom), 7.96 m
(2H, Harom), 9.82 s (1H, NH), 11.61 s (1H, NH).
13C NMR spectrum, δC, ppm: 22.8 (Me), 95.3 (C3);
122.6, 125.1, 125.9, 127.1, 128.2, 128.5, 128.9, 130.3,
131.9, 138.5 (Carom); 151.9 (C2), 165.2 (COOH), 168.8
(CONH), 189.3 (COPh). Mass spectrum: m/z 325.15
[M + H]+. Found, %: C 66.59; H 4.87; N 8.44.
C18H16N2O4. Calculated, %: C 66.66; H 4.97; N 8.64.
[M + H]+ 325.12.
from EtOH). IR spectrum, ν, cm–1: 3182 br (NH), 1739
1
(C1=O, C4=O), 1664 (C1′=O). H NMR spectrum, δ,
ppm: 0.96 t (3H, CH2Me, J = 7.1 Hz), 1.23 t (3H,
CH2Me, J = 7.1 Hz), 2.08 s (3H, MeCONH), 4.02 q
(2H, OCH2, J = 7.1 Hz), 4.14 q (2H, OCH2, J =
7.1 Hz), 5.22 s (1H, 3-H), 6.81 m (1H, Harom), 7.13 m
(2H, Harom), 7.26 m (1H, Harom), 9.40 s (1H, NH),
9.88 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.2
(CH2Me), 14.1 (CH2Me), 22.8 (MeCONH), 59.3
(OCH2), 61.5 (OCH2), 93.4 (C3); 122.6, 124.8, 125.1,
125.7, 130.6, 135.1 (Carom); 148.0 (C2), 163.8 (C4),
167.4 (C1), 168.7 (MeCONH). Mass spectrum:
m/z 321.14 [M + H]+. Found, %: C 60.03; H 6.37;
N 8.65. C16H20N2O5. Calculated, %: C 59.99; H 6.29;
N 8.74. [M + H]+ 321.15.
Compounds 2b and 2c were synthesized in
a similar way.
Methyl (2Z)-2-(2-acetamidoanilino)-4-oxo-4-
phenylbut-2-enoate (2b). Yield 1.28 g (73%),
mp 167–168°C (decomp., from EtOH). IR spectrum, ν,
cm–1: 3172 br (NH), 1731 (C1=O), 1663 (C4=O,
C19
C18
N2
H2A
C17
O4
1
C1′=O). H NMR spectrum, δ, ppm: 2.10 s (3H,
C16
C15
C14
MeCONH), 3.66 s (3H, OMe), 6.47 s (1H, 3-H),
6.95 m (1H, Harom), 7.19 m (2H, Harom), 7.32 m (1H,
Harom), 7.52 m (2H, Harom), 7.60 m (1H, Harom), 7.98 m
(2H, Harom), 9.85 s (1H, NH), 11.51 s (1H, NH).
13C NMR spectrum, δC, ppm: 22.8 (MeCONH), 52.7
(OMe), 96.3 (C3); 122.6, 125.4, 125.8, 126.0, 127.1,
128.3, 128.5, 130.6, 132.1, 138.2 (Carom); 149.3 (C2),
164.2 (COOMe), 168.8 (CONH), 189.4 (COPh). Mass
spectrum: m/z 339.18 [M + H]+. Found, %: C 67.53;
H 5.33; N 8.15. C19H18N2O4. Calculated, %: C 67.45;
H 5.36; N 8.28. [M + H]+ 339.13.
H1
C12
O1
N1
C11
C10
C6
C1
C13
O3
C3
C4
C2
C7
C9
O2
C5
C8
Fig. 1. Structure of the molecule of methyl (2Z)-2-(2-acet-
amidoanilino)-4-oxo-4-phenylbut-2-enoate (2b) according to
the X-ray diffraction data. Non-hydrogen atoms are shown as
thermal vibration ellipsoids with a probability of 50%.
Diethyl (2Z)-2-(2-acetamidoanilino)but-2-enedi-
oate (2c). Yield 1.15 g (69%), mp 99–101°C (decomp.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 3 2019

STEPANOVA et al.
404
(3Z)-3-(2-Oxo-2-phenylethylidene)-3,4-dihydro-
points were measured in open capillaries with
a Mettler Toledo MP90 melting point apparatus. The
reaction conditions were optimized by UHPLC
(Waters Acquity UPLCI-Class; Acquity UPLC BEH
C18 column, grain size 1.7 μm; eluent acetonitrile–
water, flow rate 0.6 mL/min; Acquity UPLC PDA el
diode array detector, λ 230–780 nm; XevoTQD mass-
selective detector, positive electrospray ionization, ion
source temperature 150°C, capillary voltage 3500–
4000 V, cone voltage 20–70 V, vaporizer temperature
150–300°C) and HPLC (Hitachi Chromaster;
Nucleodur C18 Gravity column, 5 μm; eluent
acetonitrile–water, flow rate 1.5 mL/min; Hitachi
Chromaster 5430 diode array detector, λ 210–750 nm).
The purity of the isolated compounds was checked
by TLC on Silicagel 60 F254 plates (Merck); eluent
toluene, ethyl acetate, or toluene–ethyl acetate (5:1);
spots were visualized by treatment with iodine vapor
or under UV light (λ 254 nm).
qunoxalin-2(1H)-one (3a). a. Compound 2a, 0.50 g
(1.5 mmol), was heated for 1 h at 140°C. The product
was recrystallized from 1,4-dioxane. Yield 0.30 g
(68%), mp 266–267°C (decomp., from 1,4-dioxane).
b. Compound 2b, 0.50 g (1.5 mmol), was heated for
2 h at 170°C. The product was recrystallized from
1,4-dioxane. Yield 0.30 g (71%), mp 266–267°C
(decomp., from 1,4-dioxane) [4].
Ethyl (2Z)-2-(3-oxo-3,4-dihydroquinoxalin-
2(1H)-ylidene)acetate (3b). Compound 2c, 0.50 g
(1.6 mmol), was heated for 3 h at 140°C. The product
was recrystallized from 1,4-dioxane. Yield 0.24 g
(71%), mp 208–210°C (decomp., from 1,4-dioxane);
published data [3]: mp 206–208°C (from EtOH).
X-Ray analysis of compound 2b. The X-ray dif-
fraction data for compound 2b were obtained on
an Xcalibur Ruby single-crystal diffractometer with
a CCD detector according to standard procedure
[Mo Kα radiation, 295(2) K, ω-scanning with a step
of 1°]. A correction for absorption was applied
empirically by SCALE3 ABSPACK algorithm [15].
Orthorhombic crystal system, space group Pbca;
C19H18N2O4, M 338.35; unit cell parameters: a =
13.736(3), b = 9.3940(17), c = 27.201(8) Å; V =
3509.9(14) Å3; Z = 8, dcalc = 1.281 g/cm3; μ =
0.091 mm–1. The structure was solved by the direct
method (SHELXS) [16] and was refined against F2 by
the full-matrix least-squares method in anisotropic
approximation for all non-hydrogen atoms (SHELXL)
[17] using OLEX2 graphical interface [18]. Hydrogen
atoms of the NH groups were refined independently in
isotropic approximation. The positions of the other
hydrogens were refined according to the riding model.
Final divergence factors: R1 = 0.0562, wR2 = 0.1306
[for 2384 reflections with I > 2σ(I)]; R1 = 0.1071,
wR2 = 0.1537 (for 4195 independent reflections);
goodness of fit S = 1.024. The X-ray diffraction
data for compound 2b were deposited to the
Cambridge Crystallographic Data Centre (CCDC
entry no. 1 866 129) and are available at
www.ccdc.cam.ac.uk/data_request/cif.
FUNDING
This study was performed under financial support
by the Russian Science Foundation (project no. 17-73-
10210).
CONFLICT OF INTERESTS
The authors declare the absence of conflict of
interests.
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