Synthesis of Dicarboxylic Acid Amides and Diamides on the Basis of [4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-yl]methanamine

Article abstract of DOI:10.1134/S1070428018060106

The condensation of various nonaromatic amines with ethyl N-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl}oxamate prepared from [4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methanamine and diethyl oxalate afforded the corresponding N,N'-disubstitut

Full text of DOI:10.1134/S1070428018060106

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 6, pp. 886–891. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © A.A. Aghekyan, G.G. Mkryan, R.E. Muradyan, A.E. Tumajyan, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No.
6, pp. 884–889.
Synthesis of Dicarboxylic Acid Amides and Diamides
on the Basis of [4-(4-Methoxyphenyl)tetrahydro-
2H-pyran-4-yl]methanamine
A. A. Aghekyana,* G. G. Mkryana, R. E. Muradyana, and A. E. Tumajyana
a Mndzhoyan Institute of Fine Organic Chemistry, Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
*e-mail: aaghekyan@mail.ru
Received November 22, 2017
Abstract—The condensation of various nonaromatic amines with ethyl N-{[4-(4-methoxyphenyl)tetrahydro-
2H-pyran-4-yl]methyl}oxamate prepared from [4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methanamine
and diethyl oxalate afforded the corresponding N,N′-disubstituted oxamides. N-Aryloxamides were synthesized
by the reaction of [4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methanamine with ethyl N-aryloxamates.
The condensation of N-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl}succinamic acid with primary
amines gave N,N′-disubstituted siccinamides.
DOI: 10.1134/S1070428018060106
Recent studies have shown that some compounds
containing an aryltetrahydropyranylmethylamino frag-
ment possess diverse biological activity [1, 2]. It is
also known that oxalic and succinic monoamides, as
well as the corresponding esters and diamides exhibit
high pharmacological activity in combination with low
toxicity [3]. Antimicrobial [4], analgesic [5], antico-
agulant [6], and anti-inflammatory agents [7] have
been found among these compounds.
amides 3a–3e (Scheme 1). The hydrolysis of 2 in al-
kaline medium gave amido acid 4, whereas its hydrol-
ysis with aqueous HCl involved the amide fragment
with the formation of initial amine 1 hydrochloride.
The hydrolysis of the amide group 2 in the presence of
HBr was accompanied by demethylation to produce
hydrobromide 5.
Our attempts to obtain N,N′-disubstituted oxamides
from amido ester 2 and aromatic amines were unsuc-
cessful. Therefore, N-aryloxamides 7a–7f were synthe-
sized by fusion of amine 1 with ethyl N-aryloxamates
6a–6f; the latter were prepared in turn by treatment of
diethyl oxalate with substituted anilines [9, 10]
(Scheme 2).
In continuation of studies in this line we have
synthesized new dicarboxylic acid derivatives contain-
ing an aryltetrahydropyranylmethyl fragment, in par-
ticular new oxalic and succinic mono- and diamides.
The key starting compound in these syntheses was
[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]meth-
anamine (1) [8].
In order to obtain succinamide derivatives, amine 1
was reacted with succinic anhydride. As a result,
succinamic acid 8 was isolated. However, we failed to
convert it to the corresponding ethyl ester by treatment
with ethanol in the presence of a catalytic amount of
sulfuric acid. Instead, intramolecular cyclization prod-
uct, N-substituted succinimide 9 was formed in a high
yield (~90%). Diamides 10a–10d were synthesized by
fusion of amido acid 8 with primary amines at 150–
160°C (Scheme 3).
The reaction of 1 with 5-equiv of diethyl oxalate
gave N-substituted ethyl oxamate 2 which was treated
with various primary amines and subjected to hydrol-
ysis in alkaline and acidic medium. Depending on the
amine nature (nonaromatic amines and substituted
anilines), the corresponding N,N′-substituted oxamides
were obtained in different ways. The condensation of
2 with nonaromatic amines, namely methanamine,
2-aminoethanol, 3-(morpholin-4-yl)propan-1-amine,
(1-phenylcyclopentyl)mehtanamine, and [1-(3,4-dime-
thoxyphenyl)cyclopentyl]methanamine afforded di-
All isolated compounds were white crystalline
solids whose structure and purity were confirmed by
spectral methods and TLC data. The newly synthesized
886

SYNTHESIS OF DICARBOXYLIC ACID AMIDES AND DIAMIDES
887
Scheme 1.
O
O
H
N
RNH2
NHR
O
MeO
3a–3e
O
O
H
N
NaOH
O
O
OH
O
O
H
(COOEt)2
MeO
N
OEt
4
NH2
O
O
MeO
MeO
1
2
HBr
HCl
NH2 · HBr
HO
5
1·HCl
R = Me (a), HOCH2CH2 (b), 3-(morpholin-4-yl)propyl (c), (1-phenylcyclopentyl)methyl (d),
[1-(3,4-dimethoxyphenyl)cyclopentyl]methyl (e).
Scheme 2.
O
O
H
O
N
H
N
R
1
OEt
R
N
O
H
O
MeO
6a–6f
7a–7f
R = 3-Br (a), 4-F (b), 4-Me (c), 4-MeO (d), 2,4-(MeO)2 (e), 4-COOEt (f).
Scheme 3.
O
O
N
H+, EtOH
O
O
MeO
O
O
O
H
O
9
N
1
OH
O
O
MeO
O
RNH2
H
8
N
NHR
O
MeO
10a–10d
R = PhCH2 (a), 4-ClC6H4CH2 (b), PhCH2CH2 (c), 3,4-(MeO)2C6H3CH2CH2 (d).
compounds were tested for anti-inflammatory (acute
and chronic) and analgesic activity in carrageenan-
induced edema and cotton pellet granuloma models
[11] upon oral administration at doses of 5 and
25 mg/kg; diclofenac (10 mg/kg) and indometacin
(3 mg/kg) were used as reference drugs. None of the
compounds showed pronounced anti-inflammatory or
analgesic activity at the given doses.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 6 2018

AGHEKYAN et al.
7.25 m (2H each, Harom), 7.46 br.t (1H, NH, J =
888
EXPERIMENTAL
6.5 Hz), 8.45 br.q (1H, NH, J = 5.0 Hz). Found, %:
C 62.51; H 7.08; N 9.43. C16H22N2O4. Calculated, %:
C 62.73; H 7.24; N 9.14.
The IR spectra were recorded in mineral oil on
a Nicolet Avatar 330 FT-IR spectrometer. The H and
1
13C NMR spectra were measured on a Varian Mercury-
300 spectrometer at 300 MHz using DMSO-d6 as
solvent and tetramethylsilane as internal standard. The
melting points were determined with Boetius micro hot
stage. Analytical thin-layer chromatography was per-
formed on Silufol UV-254 plates; spots were visual-
ized by treatment with iodine vapor.
N-(2-Hydroxyethyl)-N′-{[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-yl]methyl}oxamide (3b).
Yield 69%, mp 80–81°C (from PhH), Rf 0.50 (ben-
1
zene–acetone, 2:1). H NMR spectrum, δ, ppm:
1.81 d.d.d (2H, CH2, J = 13.9, 8.9, 3.5 Hz), 1.97–
2.06 m (2H, CH2), 3.23 q (2H, NHCH2CH2O, J =
5.7 Hz), 3.32 d (2H, NCH2C, J = 6.5 Hz), 3.40 d.d.d
(2H, OCH2, J = 11.5, 9.1, 2.6 Hz), 3.46 q (2H, OCH2,
J = 5.7 Hz), 3.64–3.72 m (2H, OCH2), 3.78 s (3H,
OCH3), 4.43 t (1H, OH, J = 5.7 Hz), 6.85–6.90 m and
7.21–7.26 m (2H each, Harom), 7.45 br.t (1H, NH, J =
6.5 Hz), 8.44 br.t (1H, NH, J = 5.7 Hz). Found, %:
C 60.91; H 7.37; N 8.12. C17H24N2O5. Calculated, %:
C 60.70; H 7.19; N 8.33.
Ethyl 2-({[4-(4-methoxyphenyl)tetrahydro-2H-
pyran-4-yl]methyl}amino)-2-oxoacetate (2). A solu-
tion of 73.0 g (0.5 mol) of diethyl oxalate in 200 mL of
chloroform was heated to the boiling point, and
a solution of 22.1 g (0.1 mol) of amine 1 [8] in 100 mL
of chloroform was slowly added dropwise. The mix-
ture was refluxed for 10 h, the solvent and excess
diethyl oxalate were distilled off, and the residue was
distilled under reduced pressure. Yield 27.0 g (84%),
bp 235–240°C (1 mm), mp 69–70°C (from Et2O–
hexane, 1:2), Rf 0.59 (benzene–acetone, 10:1). IR
spectrum, ν, cm–1: 3317 (NH), 1744 (C=O, ester), 1683
N-{[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}-N′-[3-(morpholin-4-yl)propyl]oxamide
(3c). Yield 67%, mp 115–117°C (from PhH), Rf 0.52
1
(benzene–acetone, 3:1). H NMR spectrum, δ, ppm:
1
1.70 m (2H, CH2CH2CH2), 1.81 d.d.d (2H, CH2, J =
13.9, 8.9, 3.5 Hz), 1.97–2.06 m (2H, CH2), 2.33–
2.40 m [6H, N(CH2)3], 3.22 t.d (2H, NHCH2CH2,
J 6.5, 5.8 Hz), 3.33 d (2H, CH2NH, J = 6.6 Hz),
3.43 d.d.d (2H, OCH2, J = 11.5, 9.0, 2.6 Hz), 3.59–
3.63 m [4H, O(CH2)2], 3.66–3.74 m (2H, OCH2), 3.79 s
(3H, OCH3), 6.84–6.89 m and 7.20–7.25 m (2H each,
(C=O, amide). H NMR spectrum, δ, ppm: 1.34 t (3H,
CH2CH3, J = 7.1 Hz), 1.82 d.d.d (2H, CH2C, J = 14.0,
8.8, 3.7 Hz), 1.96–2.05 m (2H, CH2C), 3.33 d (2H,
CH2NH, J = 6.6 Hz), 3.45 d.d.d (2H, CH2O, J = 11.5,
8.8, 2.7 Hz), 3.70 d.d.d (2H, CH2O, J = 11.5, 5.3,
3.7 Hz), 3.80 s (3H, OCH3), 4.22 q (2H, OCH2CH3,
J = 7.1 Hz), 6.84–6.89 m and 7.20–7.25 m (2H each,
Harom), 7.71 t (1H, NH, J = 6.6 Hz). Found, %:
C 63.68; H 7.08; N 4.54. C17H23NO5. Calculated, %:
C 63.54; H 7.21; N 4.36.
Harom), 7.58 br.t (1H, NH, J = 6.5 Hz), 8.77 br.t (1H,
NH, J = 6.6 Hz). Found, %: C 62.67; H 7.72; N 10.31.
C22H33N3O5. Calculated, %: C 62.99; H 7.93; N 10.02.
N-{[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}-N′-[(1-phenylcyclopentyl)methyl]ox-
amide (3d). Yield 75%, mp 114–116°C (from PhMe),
Oxamides 3a–3e (general procedure). A mixture of
1.6 g (5 mmol) of ester 2 and 5 mmol of the corre-
sponding amine in 30 mL of ethanol was refluxed for
8 h (in the reaction with methylamine, the mixture was
kept for 18 h at room temperature). The solvent was
distilled off, the residue was treated with hexane, and
the precipitate was filtered off and recrystallized from
an appropriate solvent.
1
Rf 0.59 (benzene–acetone, 3:1). H NMR spectrum, δ,
ppm: 1.62–2.14 m (12H, C5H8, CH2CCH2), 3.28 d (2H,
NCH2, J = 6.5 Hz), 3.31 d (2H, NCH2, J = 6.6 Hz),
3.41 d.d.d (2H, OCH2, J = 11.4, 9.0, 2.5 Hz), 3.64–
3.72 m (2H, OCH2), 3.79 s (3H, OCH3), 6.83–6.88 m
(2H, Harom), 7.14–7.31 m (7H, Harom), 7.47 br.t (1H,
NH, J = 6.5 Hz), 7.63 br.t (1H, NH, J = 6.6 Hz).
Found, %: C 71.69; H 7.75; N 6.17. C27H34N2O4. Cal-
culated, %: C 71.97; H 7.61; N 6.22.
N-{[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}-N′-methyloxamide (3a). Yield 70%,
mp 115–117°C (from EtOH), Rf 0.48 (benzene–ace-
tone, 3:1). IR spectrum, ν, cm–1: 3350 (NH), 1693,
1
1658 (C=O), 1610, 1590 (C=Carom). H NMR spec-
N-{[1-(3,4-Dimethoxyphenyl)cyclopentyl]meth-
yl}-N′-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}oxamide (3e). Yield 73%, mp 118–120°C
(from PhMe), Rf 0.55 (benzene–acetone, 3 : 1).
1H NMR spectrum, δ, ppm: 1.64–2.04 m (12H, C5H8,
CH2CCH2), 3.27 d (2H, NCH2, J = 6.5 Hz), 3.28 d
trum, δ, ppm: 1.85 d.d.d (2H, CH2, J = 13.8, 9.0,
3.5 Hz), 2.00–2.06 m (2H, CH2), 2.71 d (3H, NCH3,
J = 5.0 Hz), 3.40 d (2H, NCH2, J = 6.6 Hz), 3.44 d.d.d
(2H, OCH2, J = 11.6, 8.9, 2.5 Hz), 3.68–3.76 m (2H,
OCH2), 3.79 s (3H, OCH3), 6.84–6.89 m and 7.20–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 6 2018

SYNTHESIS OF DICARBOXYLIC ACID AMIDES AND DIAMIDES
889
(2H, NCH2, J = 6.6 Hz), 3.40 d.d.d (2H, OCH2, J =
11.5, 9.1, 2.6 Hz), 3.64–3.72 m (2H, OCH2), 3.78 s
(3H, OCH3), 3.79 s (3H, OCH3), 3.79 s (3H, OCH3),
6.71–6.80 m (3H, C6H3), 6.83–6.88 m and 7.16–
7.21 m (2H each, C6H4), 7.47 br.t (1H, NH, J =
6.5 Hz), 7.63 br.t (1H, NH, J = 6.6 Hz). Found, %:
C 68.49; H 7.36; N 5.21. C29H38N2O6. Calculated, %:
C 68.21; H 7.50; N 5.49.
ppm: 1.84 d.d.d (2H, CH2, J = 13.9, 9.5, 3.6 Hz),
2.14 br.d (2H, CH2, J = 13.9 Hz), 2.92 q (2H, NCH2,
J = 5.6 Hz), 3.41 d.d.d (2H, OCH2, J = 11.4, 9.5,
2.0 Hz), 3.68 d.d.d (2H, OCH2, J = 11.4, 4.3, 3.6 Hz),
6.76–6.82 m and 7.11–7.18 m (2H each, Harom),
7.70 br.t (3H, NH2, HBr, J = 5.6 Hz), 9.07 br (1H,
OH). Found, %: C 50.37; H 6.49; Br 27.52; N 4.67.
C12H17NO2 ·HBr. Calculated, %: C 50.01; H 6.30;
Br 27.73; N 4.86.
2-({[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}amino)-2-oxoacetic acid (4). A mixture
of 1.9 g (6 mmol) of amido ester 2 and 20 mL of 20%
aqueous sodium hydroxide was stirred for 5 h at 35–
40°C. The resulting transparent solution was acidified,
and the precipitate was filtered off, washed with water,
dried, and recrystallized from benzene. Yield 1.3 g
(75%), mp 102–103°C, Rf 0.43 (benzene–acetone,
1:1). IR spectrum, ν, cm–1: 3289 (NH), 3217–3081
(OH), 1751 (C=O, acid), 1685 (C=O, amide). 1H NMR
spectrum, δ, ppm: 1.84 d.d.d (2H, CH2, J = 13.8, 9.0,
3.5 Hz), 2.00–2.09 m (2H, CH2), 3.35 d (2H, NCH2,
J = 6.6 Hz), 3.44 d.d.d (2H, OCH2, J = 11.6, 8.9,
2.5 Hz), 3.68–3.76 m (2H, OCH2), 3.79 s (3H, OCH3),
6.84–6.89 m and 7.22–7.27 m (2H each, Harom), 7.77 t
(1H, NH, J = 6.5 Hz), 12.41 br (1H, OH). Found, %:
C 61.74; H 6.37; N 4.59. C15H19NO5. Calculated, %:
C 61.42; H 6.53; N 4.78.
Oxamides 7a–7f (general procedure). A mixture of
1.1 g (5 mmol) of amine 1 and 5 mmol of anilido ester
6a–6f was heated for 5 h at 120–125°C. The resulting
solid was treated with hexane, and the precipitate was
filtered off, washed with water, 10% aqueous HCl, and
water again, dried in air, and recrystallized from
ethanol.
N-(3-Bromophenyl)-N′-{[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-yl]methyl}oxamide (7a).
Yield 80%, mp 150–152°C, Rf 0.55 (benzene–acetone,
1
5:1). H NMR spectrum, δ, ppm: 1.85 d.d.d (2H, CH2,
J = 14.0, 8.9, 3.6 Hz), 2.00–2.09 m (2H, CH2), 3.40 d
(2H, NCH2, J = 6.6 Hz), 3.44 d.d.d (2H, OCH2, J =
11.7, 8.9, 2.6 Hz), 3.68–3.76 m (2H, OCH2), 3.79 s
(3H, OCH3), 6.85–6.90 m (2H) and 7.21–7.26 m (2H,
MeOC6H4); 7.15–7.21 m (2H), 7.74–7.81 m (1H), and
8.09–8.11 m (1H) (BrC6H4); 7.84 br.t (1H, NHCH2,
J = 6.6 Hz), 10.61 s (1H, NH). Found, %: C 56.62;
H 5.31; Br 17.65; N 6.09. C21H23BrN2O4. Calculated,
%: C 56.39; H 5.18; Br 17.86; N 6.26.
[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-
yl]methanamine hydrochloride (1·HCl). A suspen-
sion of 1.6 g (5 mmol) of amido ester 2 in 50 mL of
concentrated aqueous HCl was refluxed for 24 h. The
mixture was evaporated to dryness, and the residue
was crystallized with acetone and recrystallized from
ethanol. Yield 0.8 g (63%), mp 275–277°C, Rf 0.51
N-(4-Fluorophenyl)-N′-{[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-yl]methyl}oxamide (7b).
Yield 78%, mp 191–193°C, Rf 0.56 (benzene–acetone,
1
1
5:1). H NMR spectrum, δ, ppm: 1.85 d.d.d (2H, CH2,
(butan-1-ol–AcOH–water, 5:3:3). H NMR spectrum,
J = 13.8, 9.0, 3.5 Hz), 2.00–2.09 m (2H, CH2), 3.40 d
(2H, NCH2, J = 6.6 Hz), 3.44 d.d.d (2H, OCH2, J =
11.6, 8.9, 2.5 Hz), 3.68–3.76 m (2H, OCH2), 3.79 s
(3H, OCH3), 6.85–6.90 m and 7.22–7.27 m (2H each,
MeOC6H4), 6.94–7.03 m and 7.80–7.87 m (2H each,
FC6H4), 7.87 br.t (1H, NHCH2, J = 6.6 Hz), 10.51 s
(1H, NH). Found, %: C 65.03; H 6.19; N 7.39.
C21H23FN2O4. Calculated, %: C 65.27; H 6.00; N 7.25.
δ, ppm: 1.91 d.d.d (2H, CH2, J = 14.0, 9.6, 3.5 Hz),
2.17 br.d (2H, CH2, J = 14.0 Hz), 2.92 s (2H, NCH2),
3.40 d.d.d (2H, OCH2, J = 11.5, 9.6, 2.0 Hz),
3.71 d.d.d (2H, OCH2, J = 11.5, 4.5, 3.5 Hz), 3.79 s
(3H, OCH3), 6.86–6.92 m and 7.26–7.32 m (2H each,
Harom), 8.08 br (3H, NH2, HCl). Found, %: C 60.37;
H 7.64; Cl 13.92; N 5.65. C13H19NO3·HCl. Calculated,
%: C 60.58; H 7.82; Cl 13.75; N 5.43.
[4-(4-Hydroxyphenyl)tetrahydro-2H-pyran-4-
yl]methanamine hydrobromide (5). A suspension of
2.5 g (8 mmol) of amido ester 2 in 75 mL of 40%
aqueous HBr was refluxed for 10 h. Water was dis-
tilled off, cold acetone was added to the residue, and
the precipitate was filtered off, washed on a filter with
cold water, dried, and recrystallized from ethanol.
Yield 1.3 g (58%), mp 262–264°C, Rf 0.45 (butan-1-
N-{[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}-N′-(4-methylphenyl)oxamide (7c).
Yield 69%, mp 170–172°C, Rf 0.54 (benzene–acetone,
1
5:1). H NMR spectrum, δ, ppm: 1.85 d.d.d (2H, CH2,
J = 14.0, 8.9, 3.5 Hz), 1.99–2.09 m (2H, CH2), 2.31 s
(3H, CH3), 3.39 d (2H, NCH2, J = 6.6 Hz), 3.44 d.d.d
(2H, OCH2, J = 11.5, 8.9, 2.5 Hz), 3.67–3.76 m (2H,
OCH2), 3.79 s (3H, OCH3), 6.85–6.90 m and 7.22–
7.27 m (2H each, MeOC6H4), 7.03–7.08 m and 7.62–
1
ol–acetic acid–water, 5:3:3). H NMR spectrum, δ,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 6 2018

AGHEKYAN et al.
890
7.67 m (2H each, MeC6H4), 7.83 br.t (1H, NHCH2, J =
6.6 Hz), 10.22 s (1H, NH). Found, %: C 69.31; H 6.71;
N 7.19. C22H26N2O4. Calculated, %: C 69.09; H 6.85;
N 7.32.
of ethyl acetate was added to a solution of 22.1 g
(0.1 mol) of amine 1 in 50 mL of ethyl acetate, and the
mixture was left to stand for 5 h at room temperature.
The mixture warmed up and became homogeneous; it
was heated for 0.5 h at 40–50°C, and the product was
precipitated with hexane, filtered off, and recrystal-
lized from diethyl ether–hexane (3:1). Yield 23.2 g
(72%), mp 142–144°C, Rf 0.51 (benzene–ethyl acetate,
1:1). IR spectrum, ν, cm–1: 3350 (NH), 2700–2500
(OH), 1707 (C=O, acid), 1611 (C=O, amide). 1H NMR
spectrum, δ, ppm: 1.80 d.d.d (2H, CH2, J = 13.9, 9.1,
3.7 Hz), 1.95 br.d (2H, CH2, J = 13.9 Hz), 2.23–2.30 m
(2H, CH2CO), 2.34–2.41 m (2H, CH2CO), 3.21 d (2H,
CH2N, J = 6.3 Hz), 3.40 d.d.d (2H, OCH2, J = 11.4,
9.1, 2.7 Hz), 3.68 d.d.d (2H, OCH2, J = 11.4, 5.0,
3.7 Hz), 3.78 s (3H, OCH3), 6.81–6.86 m and 7.17–
7.23 m (2H each, Harom), 7.06 t (1H, NH, J = 6.3 Hz),
11.76 br (1H, COOH). 13C NMR spectrum, δC, ppm:
29.1, 30.0, 32.9, 39.8, 48.7, 54.4, 63.1, 113.3, 127.4,
135.3, 157.1, 170.6, 173.4. Found, %: C 63.72;
H 7.05; N 4.21. C17H23NO5. Calculated, %: C 63.54;
H 7.21; N 4.36.
N-(4-Methoxyphenyl)-N′-{[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-yl]methyl}oxamide (7d).
Yield 77%, mp 166–168°C, Rf 0.56 (benzene–acetone,
1
5:1). H NMR spectrum, δ, ppm: 1.85 d.d.d (2H, CH2,
J = 14.0, 8.9, 3.5 Hz), 1.99–2.09 m (2H, CH2), 3.41 d
(2H, NCH2, J = 6.6 Hz), 3.43 d.d.d (2H, OCH2, J =
11.6, 9.0, 2.3 Hz), 3.67–3.75 m (2H, OCH2), 3.78 s
(3H, OCH3), 3.83 s (3H, OCH3), 6.85–6.90 m and
7.22–7.27 m (2H each, C6H4), 7.08–7.13 m and
7.61–7.66 m (2H each, C6H4), 7.58 br.t (1H, NH, J =
6.6 Hz), 10.21 s (1H, NH). Found, %: C 66.54;
H 6.71; N 6.87. C22H26N2O5. Calculated, %: C 66.32;
H 6.58; N 7.03.
N-(2,4-Dimethoxyphenyl)-N′-{[4-(4-methoxy-
phenyl)tetrahydro-2H-pyran-4-yl]methyl}oxamide
(7e). Yield 72%, mp 136–138°C, Rf 0.58 (benzene–
1
acetone, 5:1). H NMR spectrum, δ, ppm: 1.84 d.d.d
(2H, CH2, J = 14.0, 9.0, 3.6 Hz), 1.99–2.08 m (2H,
CH2), 3.38 d (2H, NCH2, J = 6.6 Hz), 3.43 d.d.d (2H,
OCH2, J = 11.6, 9.0, 2.3 Hz), 3.67–3.75 m (2H,
OCH2), 3.78 s (3H, OCH3), 3.79 s (3H, OCH3), 3.93 s
(3H, OCH3), 6.44 d.d (1H, 5-H in C6H3, J = 8.9,
2.6 Hz), 6.55 d (1H, 3-H in C6H3, J = 2.6 Hz), 6.85–
6.90 m and 7.21–7.26 m (2H each, C6H4), 7.87 br.t
(1H, NH, J = 6.6 Hz), 8.11 d (1H, 6-H in C6H3, J =
8.9 Hz), 9.48 s (1H, NH). 13C NMR spectrum, δC,
ppm: 33.0, 49.3, 54.4, 54.7, 55.4, 63.0, 98.1, 103.6,
113.6, 119.2, 119.5, 127.3, 134.3, 149.3, 156.0, 156.6,
157.4, 159.4. Found, %: C 64.71; H 6.38; N 6.37.
C23H28N2O6. Calculated, %: C 64.47; H 6.59; N 6.54.
1-{[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-
yl]methyl}pyrrolidine-2,5-dione (9). A mixture of
3.2 g (10 mmol) of amido acid 8 and 0.3 mL of 98%
sulfuric acid in 50 mL of anhydrous ethanol was
heated for 5 h. After cooling, the precipitate was fil-
tered off, washed with ethanol and water, and recrys-
tallized from ethanol. Yield 2.7 g (90%), mp 124–
125°C, Rf 0.68 (methanol). IR spectrum, ν, cm–1: 1701
1
(C=O), 1605, 1590 (C=Carom). H NMR spectrum, δ,
ppm: 1.78 d.d.d (2H, CH2, J = 14.0, 10.7, 4.0 Hz),
2.01–2.09 m (2H, CH2), 2.55 s [4H, CO(CH2)2],
3.33 d.d.d (2H, OCH2, J = 11.6, 10.8, 2.0 Hz), 3.38 s
(2H, NCH2), 3.67 d.t (2H, OCH2, J = 11.6, 3.8 Hz),
3.78 s (3H, OCH3), 6.79–6.84 m and 7.17–7.22 m (2H
Ethyl 4-[2-({[4-(4-methoxyphenyl)tetrahydro-
2H-pyran-4-yl]methyl}amino)-2-oxoacetamido]ben-
zoate (7f). Yield 78%, mp 154–156°C, Rf 0.57 (ben-
13
each, Harom). C NMR spectrum, δC, ppm: 27.4, 33.5,
41.0, 48.7, 54.4, 63.0, 113.4, 127.7, 133.1, 157.4,
176.4. Found, %: C 67.56; H 6.72; N 4.47. C17H21NO4.
Calculated, %: C 67.31; H 6.98; N 4.62.
1
zene–acetone, 5:1). H NMR spectrum, δ, ppm: 1.37 t
(3H, CH3, J = 7.1 Hz), 1.80–1.90 m (2H, CH2), 2.00–
2.09 m (2H, CH2), 3.41 d (2H, NCH2, J = 6.6 Hz),
3.44 d.d.d (2H, OCH2, J = 11.6, 9.0, 2.4 Hz), 3.68–
3.76 m (2H, OCH2), 3.79 s (3H, OCH3), 4.30 q (2H,
OCH2CH3, J = 7.1 Hz), 6.85–6.90 m and 7.22–7.27 m
(2H each, MeOC6H4), 7.88–7.96 m (5H, NHCH2,
C6H4NH), 10.70 s (1H, NH). Found, %: C 65.69;
H 6.28; N 6.52. C24H28N2O6. Calculated, %: C 65.44;
H 6.41; N 6.36.
N,N′-Disubstituted succinamides 10a–10d (gen-
eral procedure). A mixture of 1.6 g (5 mmol) of
N-substituted succininc acid monoamide 8 and 5 mmol
of the corresponding amine was heated at 150–160°C
for 30–40 min until water no longer separated. The
mixture solidified and was treated with 50 mL of
chloroform. The chloroform solution was washed with
dilute aqueous HCl (1:1), water, 5% aqueous sodium
hydroxide, and water again and dried over Na2SO4.
The solvent was distilled off, and the crystalline
4-({[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}amino)-4-oxobutanoic acid (8). A solu-
tion of 10.0 g (0.1 mol) of succinic anhydride in 50 mL residue was recrystallized from benzene.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 6 2018

SYNTHESIS OF DICARBOXYLIC ACID AMIDES AND DIAMIDES
891
N-Benzyl-N′-{[4-(4-methoxyphenyl)tetrahydro-
2H-pyran-4-yl]methyl}succinamide (10a). Yield
61%, mp 131–133°C, Rf 0.52 (benzene–acetone, 2:1).
1H NMR spectrum, δ, ppm: 1.80 d.d.d (2H, CH2, J =
13.9, 9.1, 3.7 Hz), 1.95 br.d (2H, CH2, J = 13.9 Hz),
2.26–2.37 m (4H, CH2CO), 3.20 d (2H, NCH2C, J =
6.3 Hz), 3.39 d.d.d (2H, OCH2, J = 11.4, 9.1, 2.5 Hz),
3.67 d.d.d (2H, OCH2, J = 11.4, 5.0, 3.7 Hz), 3.77 s
(3H, OCH3), 4.25 d (2H, PhCH2, J = 6.3 Hz), 6.80–
6.86 m (2H) and 7.10–7.27 m (7H) (Harom), 7.16 t (1H,
NH, J = 6.0 Hz), 8.17 t (1H, NH, J = 6.0 Hz). Found,
%: C 70.53; H 7.28; N 6.70. C24H30N2O4. Calculated,
%: C 70.22; H 7.37; N 6.82.
J = 6.3 Hz), 3.25 t.d (2H, NCH2CH2, J = 7.3, 5.4 Hz),
3.35–3.44 m (2H, CH2O), 3.64–3.72 m (2H, CH2O),
3.76 s (3H, OCH3), 3.77 s (3H, OCH3), 3.79 s (3H,
OCH3), 6.67 d.d (1H, 6-H in C6H3, J = 8.1, 1.9 Hz),
6.72 d (1H, 2-H in C6H3, J = 1.9 Hz), 6.75 d (1H, 5-H
in C6H3, J = 8.1 Hz), 6.80–6.86 m (2H, C6H4), 7.15 br.t
(1H, NH, J = 6.3 Hz), 7.17–7.23 m (2H, C6H4),
7.60 br.t (1H, NH, J = 5.4 Hz). 13C NMR spectrum, δC,
ppm: 30.9, 30.9, 32.9, 34.7, 39.7, 40.1, 48.7, 54.3,
55.1, 55.2, 63.1, 113.2, 127.4, 131.8, 135.2, 147.1,
148.6, 157.1, 170.8, 171.1. Found, %: C 66.71;
H 7.65; N 5.92. C27H36N2O6. Calculated, %: C 66.92;
H 7.49; N 5.78.
N-(4-Chlorobenzyl)-N′-{[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-yl]methyl}succinamide
(10b). Yield 60%, mp 146–148°C, Rf 0.55 (benzene–
REFERENCES
1. Arustamyan, Zh.S., Markaryan, R.E., Tsatinyan, A.S.,
Shirinyan, E.A., Asatryan, T.O., Minasyan, N.S., and
Markaryan, E.A., Khim. Zh. Arm., 2012, vol. 65, no. 3,
p. 332.
1
acetone, 2:1). H NMR spectrum, δ, ppm: 1.79 d.d.d
(2H, CH2, J = 13.9, 9.1, 3.7 Hz), 1.94 br.d (2H, CH2,
J = 13.9 Hz), 2.26–2.37 m (4H, CH2CO), 3.20 d (2H,
NCH2C, J = 6.3 Hz), 3.39 d.d.d (2H, OCH2, J = 11.4,
9.1, 2.5 Hz), 3.67 d.d.d (2H, OCH2, J = 11.4, 5.0,
3.7 Hz), 3.77 s (3H, OCH3), 4.24 d (2H, C6H4CH2,
J = 6.3 Hz), 6.80–6.86 m and 7.17–7.22 m (2H each,
MeOC6H4), 7.16 t (1H, NH, J = 6.0 Hz), 7.22–7.25 m
(4H, C6H4Cl), 8.16 t (1H, NH, J = 6.0 Hz). Found, %:
C 64.43; H 6.71; Cl 7.74; N 6.49. C24H29ClN2O4. Cal-
culated, %: C 64.78; H 6.57; Cl 7.97; N 6.30.
2. Aghekyan, A.A., Mkryan, G.G., Tsatinyan, A.S.,
Noravyan, O.S., and Gasparyan, G.V., Russ. J. Org.
Chem., 2016, vol. 52, no. 2, p. 209.
3. Koz’minykh, V.O., Pharm. Chem. J., 2006, vol. 40,
no. 1, p. 8.
4. Dolzhenko, A.V., Koz’minykh, V.O., Kolotova, N.V.,
Syropyatov, B.Ya., and Novoselova, G.N., Pharm.
Chem. J., 2003, vol. 37, no. 5, p. 229.
N-{[4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
4-yl]methyl}-N′-(2-phenylethyl)succinamide (10c).
Yield 58%, mp 148–150°C, Rf 0.53 (benzene–acetone,
5. Burdulene, D., Palaima, A., Stumbryavichyute, Z.,
Talaikite, Z., Metkalova, S.E., and Penyazeva, G.A.,
Pharm. Chem. J., 1999, vol. 33, no. 5, p. 261.
1
6. Syropyatov, B.Ya., Kolotova, N.V., and Dolzhen-
ko, A.V., Vopr. Biol., Med. Farm. Khim., 2012, vol. 5,
p. 31.
4:1). H NMR spectrum, δ, ppm: 1.80 d.d.d (2H, CH2,
J = 13.9, 9.1, 3.7 Hz), 1.95 br.d (2H, CH2, J =
13.9 Hz), 2.21–2.30 m (4H, CH2CO), 2.69–2.75 m
(2H, PhCH2), 3.21 d (2H, NCH2C, J = 6.3 Hz), 3.24–
3.32 m (2H, CH2N), 3.33–3.45 m (2H, CH2O), 3.64–
3.72 m (2H, CH2O), 3.77 s (3H, OCH3), 6.80–6.86 m
(2H) and 7.10–7.27 m (8H) (Harom, NH), 7.66 t (1H,
NH, J = 6.0 Hz). 13C NMR spectrum, δC, ppm: 30.9,
30.9, 32.9, 35.2, 39.7, 40.1, 48.7, 54.3, 63.1, 113.2,
127.4, 127.7, 128.2, 135.2, 139.1, 157.1, 170.8, 171.1.
Found, %: C 70.51; H 7.78; N 6.49. C25H32N2O4. Cal-
culated, %: C 70.73; H 7.60; N 6.60.
7. Dolzhenko, A.V., Kolotova, N.V., Koz’minykh, V.O.,
Vasilyuk, M.V., Kotegov, V.P., Novoselova, G.N.,
Syropyatov, B.Ya., and Vakhrin, M.I., Pharm. Chem. J.,
2003, vol. 37, no. 3, p. 149.
8. Aghekyan, A.A. and Mkryan, G.G., Russ. J. Gen. Chem.,
2015, vol. 85, no. 5, p. 1057.
9. Aghekyan, A.A., Panosyan, G.A., and Markaryan, E.A.,
Russ. J. Org. Chem., 2013, vol. 49, no. 7, p. 1083.
10. Vartanyan, S.O., Avakyan, A.S., Sarkisyan, A.B.,
Markaryan, E.A., Arutyunyan, S.A., Shirinyan, E.A.,
and Khachatryan, A.G., Vestn. MANEB, 2005, vol. 10,
no. 6, p. 198.
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N′-{[4-(4-me-
thoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl}-
succinamide (10d). Yield 63%, mp 160–162°C,
11. Rukovodstvo po eksperimental’nomu /doklinicheskomu/
izucheniyu novykh farmakologicheskikh veshchestv
(A Guide to Experimental /Preclinical/ Trials of New
Pharmacologically Active Compounds), Khabriev, R.U.,
Ed., Moscow: Meditsina, 2005.
1
Rf 0.56 (benzene–acetone, 4:1). H NMR spectrum, δ,
ppm: 1.79 d.d.d (2H, CH2, J = 13.9, 9.1, 3.5 Hz),
1.95 br.d (2H, CH2, J = 13.9 Hz), 2.25 s (4H, CH2CO),
2.64 t (2H, C6H3CH2, J = 7.3 Hz), 3.20 d (2H, NCH2C,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 6 2018