Derivatives of α,β-dehydro amino acids: VI. Reaction of 4-benzylidene-2-phenyl-1,3-oxazol-5(4H)-one with piperidin-2-ylmethanamine

Article abstract of DOI:10.1134/S1070428013060146

4-Benzylidene-2-phenyl-1,3-oxazol-5(4H)-one reacts with piperidin-2-ylmethanamine to give N-{(Z)-3-oxo-3-[(piperidin-2-ylmethyl)amino]- 1-phenylprop-1-en-2-yl}benzamide, N-(4-benzyl-3-oxooctahydro-2N-pyrido[1,2-a] pyrazin-4-yl)benzamide, or/and (Z)-4-benzylidenehexahydro-2H-pyrido[1,2-a] pyrazin-3(2H)-one, depending on the solvent, temperature, and reaction time. The latter product is formed via three-step tandem process.

Full text of DOI:10.1134/S1070428013060146

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 6, pp. 886–889. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © V.O. Topuzyan, A.R. Manvelyan, V.V. Grigoryan, R.A. Tamazyan, A.G. Aivazyan, 2013, published in Zhurnal Organicheskoi
Khimii, 2013, Vol. 49, No. 6, pp. 901–903.
Derivatives of α,β-Dehydro Amino Acids:
VI.* Reaction of 4-Benzylidene-2-phenyl-1,3-oxazol-5(4H)-one
with Piperidin-2-ylmethanamine
V. O. Topuzyan, A. R. Manvelyan, V. V. Grigoryan, R. A. Tamazyan, and A. G. Aivazyan
Mndzhoyan Institute of Fine Organic Chemistry, Scientific–Technological Center of Organic and Pharmaceutical
Chemistry, National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 375014 Armenia
e-mail: vtop@web.am
Received August 28, 2012
Abstract—4-Benzylidene-2-phenyl-1,3-oxazol-5(4H)-one reacts with piperidin-2-ylmethanamine to give
N-{(Z)-3-oxo-3-[(piperidin-2-ylmethyl)amino]-1-phenylprop-1-en-2-yl}benzamide, N-(4-benzyl-3-oxooctahy-
dro-2N-pyrido[1,2-a]pyrazin-4-yl)benzamide, or/and (Z)-4-benzylidenehexahydro-2H-pyrido[1,2-a]pyrazin-
3(2H)-one, depending on the solvent, temperature, and reaction time. The latter product is formed via three-step
tandem process.
DOI: 10.1134/S1070428013060146
We previously found that amino amides derived
from N-substituted α,β-dehydro amino acids undergo
intramolecular cyclization in dioxane in the presence
of potassium carbonate to produce fused heterocyclic
systems [1, 2]. In continuation of these studies, we
now report on the reaction of 4-benzylidene-2-phenyl-
1,3-oxazol-5(4H)-one (I) with piperidin-2-ylmethan-
amine (II). The reaction in ethyl acetate at room tem-
perature gave N-{(Z)-3-oxo-1-phenyl-3-[(piperidin-2-
ylmethyl)amino]prop-1-en-2-yl}benzamide (III),
whereas N-(4-benzyl-3-oxooctahydro-2H-pyrido-
[1,2-a]pyrazin-4-yl)benzamide (IV) was obtained on
heating under reflux (Scheme 1). Compound IV was
also formed when amide III was heated in dioxane
both in the presence and in the absence of K2CO3.
However, in these cases, (Z)-4-benzylidenehexahydro-
2H-pyrido[1,2-a]pyrazin-3(4H)-one (V) was isolated
from the reaction mixture in addition to benzamide IV.
Scheme 1.
O
O
O
EtOAc, room
temperature
Ph
NH
O
+
HN
H2N
Ph
N
N
HN
H
Ph
Ph
I
II
III
O
Ph
N
O
O
Ph
1,4-Dioxane (K2CO3)
reflux
HN
NH
Ph
NH
+
N
IV
V
V
EtOAc, reflux
DMF, reflux
I
+
II
IV
* For communication V, see [1].
886

DERIVATIVES OF α,β-DEHYDRO AMINO ACIDS: VI.
887
Effect of solvent on the cyclization of N-{(1Z)-3-oxo-1-
phenyl-3-[(piperidin-2-ylmethyl)amino]prop-1-en-2-yl}-
benzamide (III)
We examined how the solvent nature affects the
intramolecular cyclization of III (see table). Protic
solvents (methanol) hampered the reaction, whereas
ethyl acetate and dioxane ensured formation of IV in
good yield. However, prolonged heating of the reaction
mixture in boiling dioxane favored formation of com-
pound V. The latter was isolated as the major product
when the reaction was carried out in acetonitrile or
DMF. In DMF, 85% of V was obtained in 1 h. These
findings allowed us to conclude that unsaturated com-
pound V is formed from dehydro amino acid derivative
III through intermediate amide IV. This conclusion
was confirmed by the transformation of amide IV into
compound V on heating in boiling DMF for 1.5 h
(yield 75%).
Yield, %
Reaction Tempera-
Solvent
time, h ture, °C
IV
V
Methanol
08
29
34
34
03
19
41
29
01
065
077
077
061
101
101
101
082
145
Tracesa
65
0.
0.
0.
Ethyl acetate
Ethyl acetate
Chloroform
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Acetonitrile
DMF
76
Mixture IV/Va
62.0
Tracesa
0.
Tracesa
31.0
71.6
64.5
85.7
We also tried to obtain fused heterocyclic com-
pound V directly from 4-benzylidene-2-phenyloxazol-
5(4H)-one (I) and amine II. In fact, the reaction in
DMF afforded pyrido[1,2-a]pyrazin-3(2H)-one V.
Obviously, the latter is formed via three-step tandem
process, the last step of which is elimination of benz-
amide molecule from compound IV (Scheme 2).
0.
0.
a
According to the TLC data.
diffractometer. The unit cell parameters were deter-
mined at room temperature and were refined from
22 reflections in the range 9.4 < θ < 11.2: monoclinic
crystal system; a = 6.3076(3), b = 13.4440(2), c =
15.4067(3) Å; β = 95.33(3)°; V = 1300.8(5) Å3; space
group P21/n (Z = 4). Total of 4078 reflection intensities
were measured at 0 ≤ h ≤ 8, 0 ≤ k ≤ 18, –21 ≤ l ≤ 21,
θmax = 30 (MoKα irradiation, graphite monochromator).
All calculations were carried out using SHELXTL
software package [3]. Averaging of symmetry-equiv-
Scheme 2.
H
Ph
N
O
O
H
Ph
NH
Ph
NH
N
O
H
–PhCONH2
N
IV
V
C5
According to the X-ray diffraction data, the exo-
cyclic double C=C bond in molecule V has Z con-
figuration (Fig. 1). Compound V was also found to be
a racemic mixture of S- and R-stereoisomers linked to
dimers by hydrogen bonds N8−H8 ···O10i, the O···H
distance being 2.880(3) Å (Fig. 2). The piperidine ring
in molecule V adopts a regular chair conformation.
C4
C7
C6
N8
C3
N1
C9
C2
EXPERIMENTAL
C11
C18
C17
C12
The IR spectra were recorded on a Specord M-80
spectrometer. The 1H and 13C NMR spectra were meas-
ured on a Varian Mercury 300 instrument. The purity
of the isolated compounds was checked by TLC on
Silufol UV-254 plates using toluene–hexane–ethanol
(1:1:1) as eluent; spots were visualized under UV
light or by treatment with iodine vapor.
O10
C13
C14
C16
C15
Fig. 1. Structure of the molecule of (4Z,9aR)-4-benzylidene-
hexahydro-2H-pyrido[1,2-a]pyrazin-3(4H)-one (V) accord-
ing to the X-ray diffraction data (arbitrary atom numbering).
The X-ray diffraction data for a single crystal of V
were acquired on an Enraf–Nonius CAD-4 automatic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013

TOPUZYAN et al.
and the precipitate was filtered off, washed with 20 ml
888
of dioxane, and dried in air. Yield 0.62 g (64%),
mp 174–177°C, Rf 0.69. According to the TLC data,
the filtrate contained compound V (Rf 0.74).
O10
H8i
N8i
H8
N8
b. A solution of 1 g (4 mmol) of oxazole I and
0.46 g of amine II in 15 ml of ethyl acetate was heated
for 39 h under reflux. The precipitate was filtered off,
washed with 15 ml of ethyl acetate, and dried in air.
Yield 0.92 g (63%). The product was identical in
physicochemical characteristics to a sample obtained
as described above in a. IR spectrum, ν, cm–1: 3265,
O10i
Fig. 2. Hydrogen-bonded dimer formed by R- and S-stereo-
isomeric molecules of (Z)-4-benzylidenehexahydro-2H-pyri-
do[1,2-a]pyrazin-3(4H)-one (V) in crystal (symmetry opera-
tion i: –x, 1 – y, –z).
1
3180, 1690, 1665. H NMR spectrum, δ, ppm: 0.83
(1H), 1.23 (1H), and 1.40–1.73 (4H) (CH2); 1.77 d.d
(1H, CH2, J = 11.7, 10.6 Hz), 2.25 t.d (1H, CH2, J =
12.1, 2.3 Hz), 2.68 d.d.d (1H, CH2, J = 11.7, 5.6,
3.4 Hz), 3.00 d (1H, CH2, J = 12.4 Hz), 3.07 d (1H,
CH2, J = 12.4 Hz), 3.13 m (1H, CH2), 3.31 t.t (1H, CH,
J = 10.6, 2.9 Hz), 7.15–7.24 m (5H, C6H5), 7.34 d (1H,
C6H5, J = 5.6 Hz), 7.50–7.38 m (3H, C6H5), 7.89 m
(2H, C6H5), 8.06 s (1H, NH). Found, %: C 72.56;
H 6.67; N 11.69. C22H25N3O2. Calculated, %: C 72.74;
H 6.94; N 11.57.
alent reflections left 3768 independent reflections
(Rint = 0.028), 2160 of which were characterized by I >
2σ(I). The structure was solved by the direct method
and was refined by the full-matrix least-squares proce-
dure in anisotropic approximation for non-hydrogen
atoms. The positions of hydrogen atoms were deter-
mined by the Fourier difference syntheses and were
refined in isotropic approximation. The final diver-
gence factor was R = 0.067; goodness of fit S = 1.05.
The set of crystallographic data for compound V (as cif
file) was deposited to the Cambridge Crystallographic
Data Centre (entry no. CCDC 891800).
(Z)-4-Benzylidenehexahydro-2H-pyrido[1,2-a]-
pyrazin-3(4H)-one (V). a. A solution of 0.5 g
(1.3 mmol) of compound III in 5 ml of DMF was
heated for 1 h under reflux. The mixture was cooled
and diluted with 20 ml of water, and the precipitate
was filtered off. Yield 0.28 g (85%), mp 232–235°C,
Rf 0.74.
N-{(Z)-3-Oxo-1-phenyl-3-[(piperidin-2-yl-
methyl)amino]prop-1-en-2-yl}benzamide (III).
A mixture of 1.0 g (4 mmol) of 4-benzylidene-2-
phenyl-1,3-oxazol-5(4H)-one (I) [4] and 0.46 g
(4 mmol) of piperidin-2-ylmethanamine (II) in 20 ml
of ethyl acetate was stirred for 24 h at room tempera-
ture. The solid material was filtered off, washed with
diethyl ether (40 ml), and dried in air. Yield 1.15 g
(79%), mp 149–151°C (from ethyl acetate), Rf 0.16. IR
b. Amine II, 0.46 g (4 mmol), was added to
a solution of 1.0 g (4 mmol) of oxazolone I in 10 ml of
dimethylformamide, and the mixture was heated for
1 h under reflux. The mixture was cooled and diluted
with 20 ml of water, and the precipitate was filtered
off, washed with diethyl ether (30 ml), and dried in air.
Yield 0.75 g (77%).
spectrum, ν, cm–1: 3284, 1655, 1650, 1640. H NMR
1
spectrum, δ, ppm: 1.07 m (1H, CH2), 1.25–1.43 m (2H,
CH2), 1.64–1.47 m (2H, CH2), 1.77 m (1H, CH2),
2.03 br.s (1H, NH), 2.56 m (1H, CH2), 2.64 m (1H,
CH), 2.97 m (1H, CH2), 3.03 d.d.d (1H, CH2, J = 13.0,
7.7, 6.1 Hz), 3.21 d.d.d (1H, CH2, J = 13.0, 5.6,
4.4 Hz), 7.13 s (1H, CH=C), 7.22–7.34 m (3H, C6H5),
7.57–7.42 m (5H, C6H5), 7.81 d.d (1H, CH2, J = 6.1,
5.6 Hz), 8.00 m (2H, C6H5), 9.76 br.s (1H, NHCOPh).
Found, %: C 72.49; H 6.80; N 11.41. C22H25N3O2. Cal-
culated, %: C 72.74; H 6.94; N 11.57.
c. A solution of 0.5 g (1.3 mmol) of compound IV
in 10 ml of dimethylformamide was heated for 1.5 h
under reflux. The mixture was cooled and diluted with
50 ml of water, and the precipitate was filtered off,
washed with water, and dried in air. Yield 0.25 g
(75%). Samples of V prepared by the three methods
were identical in physicochemical characteristics. IR
1
spectrum, ν, cm–1: 3170, 1665. H NMR spectrum, δ,
ppm: 1.32–1.86 m (6H, CH2), 2.46 m and 2.39 m (2H,
NCH2), 3.23–3.11 m (2H, NCH2), 3.32 d.t (1H, CH,
J = 12.5, 3.5 Hz), 6.40 s (1H, C=CH), 7.44–7.08 m
(5H, C6H5), 7.90 br.s (1H, NH). 13C NMR spectrum,
δC, ppm: 22.683, 24.244, 28.596, 38.942, 39.225,
39.500, 39.775, 40.058, 43.100, 50.153, 56.891,
N-(4-Benzyl-3-oxooctahydro-2H-pyrido[1,2-a]-
pyrazin-4-yl)benzamide (IV). a. A solution of 1 g
(2.76 mmol) of compound III in 15 ml of dioxane was
heated for 3 h under reflux. The mixture was cooled,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013

DERIVATIVES OF α,β-DEHYDRO AMINO ACIDS: VI.
889
2. Topuzyan, V.O. and Kazandzhyan, M.M., Abstracts of
Papers, XXII Mezhdunarodnaya nauchno-tekhnicheskaya
konferentsiya “Khimicheskie reaktivy, reagenty i pro-
tsessy malotonazhnoi khimii“ (XXIInd Int. Scientific–
Technical Conf. “Chemical Reagents and Processes of
Small-Scale Chemistry”). Minsk, 2010, p. 25.
110.425, 125.446, 127.315, 128.027, 136.463,
139.214, 163.934. Found, %: C 74.16; H 7.54;
N 11.72. C15H18N2O. Calculated, %: C 74.39; H 7.49;
N 11.57.
REFERENCES
3. Sheldrick, G.M., SHELXS97, SHELXL97; Göttingen,
Germany: Univ. of Göttingen, 1997.
1. Topuzyan, V.O., Kazandzhyan, M.M., Tamazyan, R.A.,
and Aivazyan, A.G., Russ. J. Org. Chem., 2009, vol. 45,
p. 215.
4. Topuzyan, V.O. and Khachvankyaan, G.Yu., Khim. Zh.
Arm., 1996, vol. 49, p. 138.
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