Synthesis of N′-substituted N-(1-phenylcyclopentylmethyl)oxamides

Full text of DOI:10.1134/S1070428013070221

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 7, pp. 1083–1086. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.A. Aghekyan, G.A. Panosyan, E.A. Markaryan, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 7,
pp. 1097–1100.
SHORT
COMMUNICATIONS
Synthesis of N′-Substituted
N-(1-Phenylcyclopentylmethyl)oxamides
A. A. Aghekyan, G. A. Panosyan, and E. A. Markaryan
Research Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
Mndzhoyan Institute of Fine Organic Chemistry, pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: aaghekyan@mail.ru
Received August 25, 2012
DOI: 10.1134/S1070428013070221
Some compounds containing a 1-phenylcyclopen-
tylmethylamino group were found to exhibit a broad
spectrum of biological activity [1]. In continuation of
these studies we have synthesized new derivatives of
(1-phenylcyclopentyl)methanamine (I) [2]. The latter
reacted with 5 equiv of diethyl oxalate [3] to give
amido ester II in 70–75% yield (Scheme 1). Alkaline
hydrolysis of II afforded amido acid III, whereas the
reduction of II with LiAlH4 led to the corresponding
amino alcohol which was characterized as hydro-
chloride IV.
metric oxamide Vi was synthesized according to
a similar scheme; it was also formed via condensation
of amine I with an equimolar amount of diethyl oxa-
late. Depending on the amine nature, the condensations
were carried out either in alcohol as solvent or by
fusion of the initial reactants.
We failed to synthesize N,N′-disubstituted oxamides
by reaction of amido ester II with substituted anilines;
therefore, the target diamides VIII were obtained as
shown in Scheme 2. The condensation of anilines
VIa–VIe with diethyl oxalate gave N-phenyl amido
esters VIIa–VIIe, and the latter reacted with amine I
to produce oxamides VIIIa–VIIIe. All compounds
synthesized in the present work were isolated as color-
less crystalline substances. Their structure and purity
were confirmed by spectral data and TLC.
We also examined reactions of II with various
amines and found that, depending on the amine nature
(alkyl-, hydroxyalkyl-, hetaryl-, and hetarylalkyl-
amines), N-(1-phenylcyclopentylmethyl)-substituted
oxamides are formed according to different schemes.
The reactions of II with amines gave unsymmetrical
oxamides Va–Vh in 60–70% yield (Scheme 1). Sym-
Ethyl 2-oxo-2-[(1-phenylcyclopentylmethyl)-
amino]acetate (II). A solution of 17.5 g (0.1 mol) of
Scheme 1.
(COOEt)2
RR'NH
O
O
R
N
OEt
NH2
N
H
N
R'
H
O
O
I
II
Va–Vi
LiAlH4
NaOH
· HCl
O
II
OH
OH
N
H
N
H
O
III
IV
R = H, R′= Bu (a); RR′N = pyrrolidin-1-yl (b), morpholin-4-yl (c); R = H, R′ = 1,3,4-thiadiazol-2-yl (d), pyridin-4-yl (e),
HOCH2CH2 (f), 3-(morpholin-4-yl)propyl (g), furfuryl (h), 1-phenylcyclopentylmethyl (i).
1083

AGHEKYAN et al.
1084
Scheme 2.
O
O
H
N
H
NH2
N
(COOEt)2
OEt
I
N
R
R
R
H
O
O
VIa–VIe
VIIa–VIIe
VIIIa–VIIIe
R = 3-Br (a), 4-Br (b), 4-F (c), 3-F3C (d), 2-MeO (e).
amine I in 100 ml of chloroform was slowly added
dropwise to a boiling solution of 73 g (0.5 mol) of
diethyl oxalate in 200 ml of chloroform. The mixture
was heated for 10 h under reflux and evaporated, and
the residue was distilled under reduced pressure. Yield
20 g (73%), bp 195–198°C (1 mm), mp 48–49°C (from
hexane), Rf 0.63 (benzene–acetone, 8:1). IR spectrum,
ν, cm–1: 3317 (NH), 1744 (C=O, ester), 1683 (C=O,
amide). Found, %: C 69.62; H 7.58; N 5.21.
C16H21NO3. Calculated, %: C 69.79; H 7.69; N 5.09.
Cl 13.95; N 5.39. C14H21NO·HCl. Calculated, %:
C 65.74; H 8.67; Cl 13.86; N 5.48.
Diamides Va–Vc (general procedure). A mixture of
10 mmol of amido ester II and 10 mmol of the
corresponding amine was heated for 5 h at 35–40°C.
The resulting solid material 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 appropriated solvent.
N-Butyl-N′-(1-phenylcyclopentylmethyl)ethane-
diamide (Va). Yield 70%, mp 108–110°C (from tolu-
2-Oxo-2-[(1-phenylcyclopentylmethyl)amino]-
acetic acid (III). A mixture of 2 g (7.2 mmol) of
amido ester II 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. Yield 1.5 g (83%), mp 98–100°C
(from benzene), Rf 0.52 (benzene–acetone, 2:1).
1H NMR spectrum, δ, ppm: 1.63–2.03 m (8H, CH2),
3.35 d (2H, NHCH2, J = 6.5 Hz), 7.17 m (1H) and
7.24–7.31 m (4H (Harom), 7.51 t (1H, NH, J = 6.5 Hz),
12.41 br.s (1H, OH). Found, %: C 68.17; H 6.83;
N 5.74. C14H17NO3. Calculated, %: C 68.00; H 6.93;
N 5.66.
1
ene), Rf 0.58 (benzene–acetone, 8:1). H NMR spec-
trum, δ, ppm: 0.92 t (3H, CH3, J = 7.2 Hz), 1.32 m
(2H, CH2CH3), 1.48 m (CH2CH2CH3), 1.66–2.02 m
(8H, CH2), 3.13 t.d (2H, NHCH2CH2, J = 6.8, 5.9 Hz),
3.35 d (2H, CH2NH, J = 6.5 Hz), 7.18 m (1H) and
7.25–7.33 m (4H) (Harom), 7.45 br.t (1H, CH2NH, J =
6.5 Hz), 8.36 br.t (1H, BuNH, J = 6.5 Hz). Found, %:
C 71.67; H 8.56; N 9.15. C18H26N2O2. Calculated, %:
C 71.49; H 8.67; N 9.26.
2-Oxo-2-(pyrrolidin-1-yl)-N-(1-phenylcyclo-
pentylmethyl)acetamide (Vb). Yield 60%, mp 106–
108°C (from hexane), Rf 0.61 (benzene–acetone, 2:1).
1H NMR spectrum, δ, ppm: 1.63–2.01 m (12H, CH2),
3.33 d (2H, NHCH2, J = 6.4 Hz), 3.38 t and 3.69 t
(2H each, NCH2, J = 6.7 Hz), 7.17 m (1H) and 7.24–
7.32 m (4H) (Harom), 7.53 br.t (1H, NH, J = 6.4 Hz).
Found, %: C 71.69; H 8.17; N 9.45. C18H24N2O2. Cal-
culated, %: C 71.97; H 8.05; N 9.33.
2-[(1-Phenylcyclopentyl)methylamino]ethanol
hydrochloride (IV). A solution of 2.75 g (10 mmol) of
amido ester II in 50 ml of benzene was added to
a mixture of 1.5 g (40 mmol) of LiAlH4 and 50 ml of
anhydrous diethyl ether, and the mixture was heated
for 12 h under reflux. When the reaction was complete,
the mixture was treated with water and filtered, and the
filtrate was evaporated. The residue was dissolved in
anhydrous diethyl ether, a solution of HCl in diethyl
ether was added, and the precipitate was filtered off
and dried. Yield 1.5 g (65%), mp 148–150°C (from
acetone), Rf 0.46 (benzene–acetone, 2 : 1, ammonia
2-(Morpholin-4-yl)-2-oxo-N-(1-phenylcyclo-
pentylmethyl)acetamide (Vc). Yield 62%, mp 101–
102°C (from heptane), Rf 0.53 (benzene–acetone, 2:1).
1H NMR spectrum, δ, ppm: 1.62–2.02 m (8H, CH2);
3.22 m (2H), 3.45 m (4H), and 3.57 m (2H)
(NCH2CH2O), 3.38 d (2H, NHCH2, J = 6.3 Hz),
7.13 m (1H) and 7.21–7.31 m (4H, Harom), 7.91 t (1H,
NH, J = 6.3 Hz). Found, %: C 68.55; H 7.48; N 8.73.
C18H24N2O3. Calculated, %: C 68.33; H 7.65; N 8.85.
1
vapor). H NMR spectrum, δ, ppm: 1.62–1.87 m and
1.98–2.19 m [4H each, (CH2)4], 2.79 m (2H,
NCH2CH2), 3.15 s (2H, NCH2), 3.63 m (2H, OCH2),
5.07 t (1H, OH, J = 5.9 Hz), 7.15–7.30 m (5H, Harom),
8.52 br.s (2H, NH, HCl). Found, %: C 65.62; H 8.80;
Diamides Vd and Ve were synthesized in a similar
way from 10 mmol of II and 10 mmol of 1,3,4-thiadi-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

SYNTHESIS OF N′-SUBSTITUTED N-(1-PHENYLCYCLOPENTYLMETHYL)OXAMIDES
1085
azol-2-amine or pyridin-4-amine by heating the reac-
tant mixture for 10 h at 65–70°C.
119°C (from toluene), Rf 0.58 (benzene–acetone, 4:1).
1H NMR spectrum, δ, ppm: 1.63–1.98 m (8H, CH2),
3.31 d (2H, NHCH2, J = 6.5 Hz), 4.31 d (2H,
NHCH2Fu, J = 6.2 Hz), 6.17 d (1H, 3′-H, J = 3.2 Hz),
6.28 d.d (1H, 4′-H, J = 3.2, 2.8 Hz), 7.14 m (1H) and
7.21–7.31 m (4H) (Harom), 7.36 d (1H, 5′-H, J =
1.8 Hz), 7.51 d (1H, NHCH2, J = 6.5 Hz), 8.34 t
(1H, NHCH2Fu, J = 6.2 Hz). Found, %: C 69.70;
H 6.90; N 8.70. C19H22N2O3. Calculated, %: C 69.92;
H 6.79; N 8.58.
N-(1-Phenylcyclopentylmethyl)-N′-(1,3,4-thiadi-
azol-2-yl)ethanediamide (Vd). Yield 67%, white crys-
tals, mp 190–191°C (from toluene), Rf 0.45 (benzene–
1
acetone, 4:1). H NMR spectrum, δ, ppm: 1.63–2.07 m
(8H, CH2), 3.44 d (2H, NCH2, J = 6.5 Hz), 7.14–
7.32 m (5H, Harom), 7.97 t (1H, NHCH2, J = 6.5 Hz),
9.05 s (1H, 5′-H), 12.72 br.s (1H, NH). Found, %:
C 58.40; H 5.38; N 16.85; S 9.58. C16H18N4O2S. Cal-
culated, %: C 58.16; H 5.49; N 16.96; S 9.70.
N,N′-Bis(1-phenylcyclopentylmethyl)ethanedi-
amide (Vi). Yield 71%, mp 160–161°C (from ethanol),
N-(1-Phenylcyclopentylmethyl)-N′-(pyridin-4-
yl)ethanediamide (Ve). Yield 61%, mp 163–165°C
(from ethanol), Rf 0.41 (benzene–acetone, 2:1).
1H NMR spectrum, δ, ppm: 1.65–2.07 m (8H, CH2),
3.42 d (2H, NCH2, J = 6.5 Hz), 7.15–7.31 m (5H,
1
Rf 0.66 (benzene–diethyl ether, 4:1). H NMR spec-
trum, δ, ppm: 1.62–2.00 m (16H, CH2), 3.31 d (4H,
NHCH2, J = 6.6 Hz), 7.14–7.31 m (10H, Harom), 7.44 t
(2H, NH, J = 6.6 Hz). Found, %: C 77.35; H 7.84;
N 6.81. C26H32N2O2. Calculated, %: C 77.19; H 7.97;
N 6.92.
Harom), 7.79 m (2H) and 8.37 m (2H) (pyridine), 7.82 t
(1H, NHCH2, J = 6.5 Hz), 10.83 s (1H, NH). Found,
%: C 70.71; H 6.40; N 12.74. C19H21N3O2. Calculated,
%: C 70.57; H 6.55; N 12.99.
Substituted anilides VIIa–VIId were synthesized as
described above for amido ester II.
Diamides Vf–Vi (general procedure). A mixture of
10 mmol of amido ester II and 10 mmol of 2-amino-
ethanol, 2-(morpholin-4-yl)ethanamine, (2-furyl)meth-
anamine, or (1-phenylcyclopentyl)methanamine in
30 ml of ethanol was heated for 8 h under reflux. After
cooling, the precipitate was filtered off.
Ethyl 2-(3-bromophenylamino)-2-oxoacetate
(VIIa). Yield 70%, mp 117–119°C (from ethanol),
Rf 0.52 (benzene–diethyl ether, 3:1). IR spectrum, ν,
cm–1: 3328 (NH), 1725 (C=O, ester), 1708 (C=O,
amide). Found, %: C 44.28; H 3.55; Br 29.20; N 5.29.
C10H10BrNO3. Calculated, %: C 44.14; H 3.70;
Br 29.37; N 5.15.
N-(2-Hydroxyethyl)-N′-(1-phenylcyclopentyl-
methyl)ethanediamide (Vf). Yield 62%, mp 132–
133°C (from ethanol), Rf 0.58 (benzene–acetone, 1:1).
1H NMR spectrum, δ, ppm: 1.63–2.02 m (8H, CH2),
3.23 q (2H, NHCH2CH2, J = 5.7 Hz), 3.36 d (2H,
NHCH2, J = 6.5 Hz), 3.48 q (2H, OCH2, J = 5.7 Hz),
4.43 t (1H, OH, J = 5.7 Hz), 7.18 m (1H) and 7.25–
7.33 m (4H) (Harom), 7.49 t (1H, NHCH2, J = 6.5 Hz),
8.30 t (1H, NHCH2CH2, J = 5.7 Hz). Found, %:
C 66.35; H 7.51; N 9.72. C16H22N2O3. Calculated, %:
C 66.18; H 7.64; N 9.65.
Ethyl 2-(4-bromophenylamino)-2-oxoacetate
(VIIb). Yield 74%, mp 155–156°C (from ethanol),
Rf 0.50 (benzene–diethyl ether, 3:1). IR spectrum, ν,
cm–1: 3333 (NH), 1731 (C=O, ester), 1707 (C=O,
amide). Found, %: C 44.28; H 3.55; Br 29.20; N 5.29.
C10H10BrNO3. Calculated, %: C 44.14; H 3.70;
Br 29.37; N 5.15.
Ethyl 2-(4-fluorophenylamino)-2-oxoacetate
(VIIc). Yield 71%, mp 110–112°C (from ethanol),
Rf 0.51 (benzene–diethyl ether, 3:1). IR spectrum, ν,
cm–1: 3319 (NH), 1734 (C=O, ester), 1688 (C=O,
amide). Found, %: C 56.75; H 4.89; F 8.91; N 6.75.
C10H10FNO3. Calculated, %: C 56.87; H 4.77; F 9.00;
N 6.63.
N-[2-(Morpholin-4-yl)ethyl]-N′-(1-phenylcyclo-
pentylmethyl)ethanediamide (Vg). Yield 60%,
mp 121–122°C (from ethanol), Rf 0.58 (benzene–
1
acetone, 3:1). H NMR spectrum, δ, ppm: 1.63–2.05 m
(8H, CH2), 2.38–2.47 m (6H, NCH2CH2), 3.26 q (2H,
NHCH2CH2, J = 6.3 Hz), 3.31 d (2H, NHCH2, J =
6.5 Hz), 3.58 m (4H, OCH2), 7.15 m (1H) and 7.23–
7.31 m (4H) (Harom), 7.48 t (1H, NHCH2, J = 6.5 Hz),
8.33 t (1H, NHCH2CH2, J = 6.3 Hz). Found, %:
C 66.55; H 8.26; N 11.81. C20H29N3O3. Calculated, %:
C 66.83; H 8.13; N 11.69.
Ethyl 2-oxo-2-(3-trifluoromethylphenylamino)-
acetate (VIId). Yield 69%, mp 118–120°C (from
ethanol), Rf 0.49 (benzene–diethyl ether, 3:1). IR spec-
trum, ν, cm–1: 3337 (NH), 1710 (C=O, ester), 1699
(C=O, amide). Found, %: C 50.39; H 3.71; F 21.63;
N 5.58. C11H10F3NO3. Calculated, %: C 50.58; H 3.86;
F 21.82; N 5.36.
N-(Furan-2-ylmethyl)-N′-(1-phenylcyclopentyl-
methyl)ethanediamide (Vh). Yield 71%, mp 118–
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AGHEKYAN et al.
1086
Ethyl 2-(2-methoxyphenylamino)-2-oxoacetate
(VIIe) was synthesized according to the procedure
described in [4].
8.0 Hz), 8.04 m (1H), and 8.28 t (1H, J = 2.0 Hz)
(C6H4); 7.74 t (1H, NHCH2, J = 6.5 Hz), 10.81 s (1H,
NHAr). Found, %: C 64.75; H 5.36; F 14.78; N 7.05.
C21H21F3N2O2. Calculated, %: C 64.61; H 5.42;
F 14.60; N 7.18.
Diamides VIIIa–VIIIe were synthesized as de-
scribed above for amides V by heating a mixture of
10 mmol of amine I and amido ester VIIa–VIIe at 65–
70°C; the products were recrystallized from ethanol.
N-(2-Methoxyphenyl)-N′-(1-phenylcyclopentyl-
methyl)ethanediamide (VIIIe). Yield 65%, mp 116–
1
118°C, Rf 0.64 (benzene–acetone, 8:1). H NMR spec-
N-(3-Bromophenyl)-N′-(1-phenylcyclopentyl-
methyl)ethanediamide (VIIIa). Yield 60%, mp 146–
trum, δ, ppm: 1.64–2.06 m (8H, CH2), 3.42 d (2H,
NHCH2, J = 6.5 Hz), 3.95 s (3H, OCH3); 6.90 m (1H),
6.96 d.d (1H, J = 8.3, 1.6 Hz), 7.06 m (1H), and
8.24 d.d (1H, J = 8.0, 1.8 Hz) (C6H4); 7.19 m (1H) and
7.27–7.33 m (4H) (Harom), 7.76 t (1H, NHCH2, J =
6.5 Hz), 9.66 s (1H, NHAr). Found, %: C 71.79;
H 6.75; N 7.87. C21H24N2O3. Calculated, %: C 71.57;
H 6.86; N 7.95.
1
148°C, Rf 0.70 (benzene–acetone, 8:1). H NMR spec-
trum, δ, ppm: 1.65–2.07 m (8H, CH2), 3.43 d (NHCH2,
J = 6.5 Hz), 7.19 m (1H) and 7.27–7.31 m (4H)
(Harom); 7.33 m (1H), 7.44 t (1H, J = 8.0 Hz), 8.04 m
(1H), and 8.28 t (1H, J = 2.0 Hz) (C6H4); 7.74 t (1H,
NHCH2, J = 6.5 Hz), 10.81 s (1H, NHAr). Found, %:
C 59.69; H 5.42; Br 19.79; N 7.12. C20H21BrN2O2.
Calculated, %: C 59.86; H 5.27; Br 19.91; N 6.98.
The IR spectra were recorded on a Nicolet Avatar
330 FT-IR spectrometer from samples dispersed in
N-(4-Bromophenyl)-N′-(1-phenylcyclopentyl-
methyl)ethanediamide (VIIIb). Yield 59%, mp 159–
1
mineral oil. The H NMR spectra were measured on
1
a Varian Mercury-300 spectrometer from solutions in
DMSO-d6 using tetramethylsilane as internal refer-
ence. The melting points were determined using
a Boetius micro-hot stage. TLC analyses were carried
out on Silufol UV-254 plates; spots were visualized by
treatment with iodine vapor.
160°C, Rf 0.70 (benzene–acetone, 8:1). H NMR spec-
trum, δ, ppm: 1.65–2.06 m (8H, CH2), 3.42 d (2H,
NHCH2, J = 6.5 Hz), 7.18 m (1H) and 7.26–7.33 m
(4H) (Harom), 7.37 m and 7.78 m (2H each, C6H4),
7.71 t (1H, NHCH2, J = 6.5 Hz), 10.55 s (1H, NHAr).
Found, %: C 59.71; H 5.40; Br 19.75; N 7.10.
C20H21BrN2O2. Calculated, %: C 59.86; H 5.27;
Br 19.91; N 6.98.
REFERENCES
N-(4-Fluorophenyl)-N′-(1-phenylcyclopentyl-
methyl)ethanediamide (VIIIc). Yield 57%, mp 140–
142°C, Rf 0.70 (benzene–acetone, 8:1). H NMR spec-
trum, δ, ppm: 1.65–2.02 m (8H, CH2), 3.40 d (2H,
NHCH2, J = 6.5 Hz), 7.18 m (1H) and 7.27–7.32 m
(4H) (Harom), 7.37 m and 7.77 m (2H each, C6H4),
7.70 t (1H, NHCH2, J = 6.5 Hz), 10.54 s (1H, NHAr).
Found, %: C 70.45; H 6.14; F 5.69; N 8.14.
C20H21FN2O2. Calculated, %: C 70.57; H 6.22; F 5.58;
N 8.23.
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N-(1-Phenylcyclopentylmethyl)-N′-(3-trifluoro-
methylphenyl)ethanediamide (VIIId). Yield 61%,
mp 134–136°C, Rf 0.67 (benzene–acetone, 8:1).
1H NMR spectrum, δ, ppm: 1.65–2.07 m (8H, CH2),
3.43 d (2H, NHCH2, J = 6.5 Hz), 7.19 m (1H) and
7.28–7.32 m (4H) (Harom); 7.33 m (1H), 7.44 t (1H, J =
3. Lambert, J.B., Huseland, D.E., and Gen-Tai Wang,
Synthesis, 1986, p. 657.
4. Vartanyan, S.O., Avakyan, A.S., Sarkisyan, A.B., Marka-
ryan, E.A., Arutyunyan, S.A, Shirinyan, E.A., and
Khachatryan, A.G., Vestn. MANEB, 2005, vol. 10, no. 6,
p. 198.
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