Synthesis of functionally substituted glutarimides

Full text of DOI:10.1134/S107036321307030X

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 7, pp. 1463–1464. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © M.S. Sargsyan, S.S. Hayotsyan, A.Kh. Khachatryan, A.E. Badasyan, S.G. Kon’kova, 2013, published in Zhurnal Obshchei Khimii,
2013, Vol. 83, No. 7, pp. 1217–1218.
LETTERS
TO THE EDITOR
Synthesis of Functionally Substituted Glutarimides
M. S. Sargsyan, S. S. Hayotsyan, A. Kh. Khachatryan, A. E. Badasyan, and S. G. Kon’kova
Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, Azatutyana ave 26, Yerevan, 0014 Armenia
e-mail: sargis@hayotsyan.com
Received March 7, 2013
DOI: 10.1134/S107036321307030X
It is known, that many compounds containing
amide or imide group exhibit versatile biological
activity. Therefore the development of new methods
for synthesis of compounds containing these pharma-
cophore groups is of particular interest. We have
recently shown that the interaction of secondary aryl-
amides of acetoacetic acid with Schiff bases resulted in
8-aryl-N,6-diaryl-3-hydroxy-1,3-dimethyl-5-oxo-2-oxa-
6-azabicyclo[2.2.2]octane-7-carboxamide [1].
ethyl 1,4-diaryl-2,6-dioxo-5-arylcarbamoylpiperidine-
3-carboxylates IV (glutarimide derivatives), containing
both amide and imide groups. It should be noted that in
the case of aldehydes yields of the product is higher
(57–84%) compared with the corresponding imines
(23–26%). The structure of the products obtained was
confirmed by the 1H and 13C NMR spectroscopy.
In both cases the interaction, probably, proceeds
through the intermediate formation of α,β-unsaturated
compound V, which adds the second molecule of
amidoester I followed by intramolecular cyclization of
the resulting adduct VII.
The reaction of ethyl 3-arylamino-3-oxopropionate
I with aromatic aldehydes II or imines III in the
presence of piperidine in refluxing ethanol results in
R1
O
O
OEt
OEt
R1
O
O
HN(CH2)5
O
O
EtO
NHR
HN(CH2)5
+ R1CHO
+
N
R2
Δ
Δ
IIa−IIc
O
N
R
O
NHR
NHR
Ia, Ib
−
IVa−IVd
IIIa, IIIb
Ia, Ib
H
O
O
O
R1
R1
R1
OEt
O
OEt
R2
EtO
NHR
OEt
N
O
O
− R2NH2
H
O
NH O
NHR
NHR
O
R
V
VI
VII
R = o-tolyl (Ia, IVa, IVb, IVc); 2,4-(CH3)2C6H3 (Ib, IVd); R1 = Ph (IIa, IIIa, IIIb, IVa, IVd), 4-Cl-C6H4 (IIb, IVb),
4-NO2-C6H4 (IIc, IVc); R2 = CH2Ph (IIIa), CH2CH2OH (IIIb).
It should be noted that similar investigations are not
known in the literature, except for one patent, where
the reaction of methyl 3-methyl-amino-3-oxopropionate
with dimethyl 2-(4-fluoro)-benzylidenemalonate is
described, leading to dimethyl 4-(4-fluoro)-phenyl-1-
methyl-2,6-dioxopiperidine-3,5-dicarboxylate [2].
1463

1464
SARGSYAN et al.
General procedure for the synthesis of the
anhydrous ethanol. Reaction time 6 h. Yield 0.3 g
(57%), mp 270°C. IR spectrum, ν, cm–1: 1670 (CОN),
1680 (O=CNC=O), 1725 (COO), 3380 (NH). 1H NMR
spectrum, δ, ppm (J, Hz): 1.09 t (3H, CH3CH2, 2J 7.5),
1.84 s (3H, CH3Ar), 2.18 s (3H, CH3Ar), 3.95–4.08 m
(2H, CH2CH3), 4.21–4.40 m (1H, 4-CH), 4.51 d (1H,
CH, J 12.5), 4.75 d (1H, CH, J 13.0), 6.95–7.16 m
(5H, o-tolyl), 7.26–7.34 m (3H, o-tolyl), 7.68–7.73 m
(2H, 4-NO2-C6H4), 8.20–8.26 m (2H, 4-NO2-C6H4),
9.53 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.6
(CH3, OEt), 16.7, 17.0 (CH3), 41.3 (C4), 54.3, 55.0 (C3,
C5), 61.1 (CH2); 123.8, 125.7, 125.8, 126.8, 126.8,
128.5, 128.8, 129.5, 130.1, 130.6 (CH, Ar); 132.6,
133.9, 135.1, 135.2, 145.1, 147.2 (Cipso, Ar); 164.7,
166.9, 167.8, 168.4 (4C=O).
substituted glutarimides (IVa–IVd). A mixture of
amide I and aldehyde II or imine III (2:1) was
refluxed in the presence of an equimolar amount of
piperidine in anhydrous ethanol for several hours. The
formed crystals were filtered off, washed with
anhydrous diethyl ether, and recrystallized from
anhydrous ethanol.
2
2
Ethyl 2,6-dioxo-4-phenyl-1-o-tolyl-5-o-tolylcar-
bamoylpiperidine-3-carboxylate (IVa) was obtained
from a mixture of 1.25 g (5.6 mmol) of amide Ia and
0.3 g (2.8 mmol) of aldehyde IIa in 15 ml of an-
hydrous ethanol. Reaction time 15 h. Yield 0.98 g
(73%), mp 230°C. IR spectrum, ν, cm–1: 1660 (CОN),
1680 (O=CNC=O), 1725 (COO), 3370 (NH). 1H NMR
spectrum, δ, ppm (J, Hz): 1.03 t (3H, CH3CH2, 2J 7.1),
1.81 s (3H, CH3Ar), 2.18 s (3H, CH3Ar), 3.99 q (2H,
CH2CH3, 2J 7.1), 4.05–4.22 m (1H, 4-CH), 4.40 d (1H,
Ethyl 2,6-dioxo-4-phenyl-1-(2,4-dimethylphenyl)-
5-(2,4-dimethylphenyl)carbamoylpiperidine-3-car-
boxylate (IVd) was obtained from a mixture of 1.12 g
(4.8 mmol) of amide Ib and 0.25 g (2.3 mmol) of
aldehyde IIa or a mixture of 1.18 g (5 mmol) of amide
Ib and 0.38 g (2.5 mmol) of imine IIIb in 15 ml of
anhydrous ethanol. Reaction time 11 or 10 h. Yield of
0.9 g (73%) or 0.3 g (23%), mp 236–237°C. IR spec-
trum, ν, cm–1: 1660 (CОN), 1675 (O=CNC=O), 1725
2
2
CH, J 12.5), 4.55 d (1H, CH, J 13.1), 6.97–7.06 m
(4H, Ph), 7.11–7.15 m (1H, Ph), 7.24–7.46 m (8H, Ph),
9.40 s (1H, NH).
Ethyl 2,6-dioxo-4-(4-chlorophenyl)-1-o-tolyl-5-o-
tolylcarbamoylpiperidine-3-carboxylate (IVb) was
obtained from a mixture of 0.88 g (4 mmol) of amide
Ia and 0.28 g (2 mmol) of aldehyde IIb or a mixture of
0.68 g (3 mmol) of amide Ia and 0.35 g (1.5 mmol) of
imine IIIa in 10 ml of anhydrous ethanol. Reaction
time 8 or 15 h. Yield 0.87 g (84%) or 0.2 g (26%), mp
260°C. IR spectrum, ν, cm–1: 1660 (CОN), 1675
(O=CNC=O), 1720 (COO), 3360 (NH). 1H NMR
spectrum, δ, ppm (J, Hz): 1.08 t (3H, CH3CH2, 2J 7.1),
1.84 s (3H, CH3Ar), 2.17 s (3H, CH3Ar), 3.98–4.08 m
(2H, CH2CH3), 4.07–4.22 m (1H, 4-CH), 4.39 d (1H,
1
(COO), 3350 (NH). H NMR spectrum, δ, ppm (J,
2
Hz): 1.03 t (3H, CH3CH2, J 7.1), 1.74 s (3H, CH3Ar),
2.13 s (3H, CH3Ar), 2.23 s (3H, CH3Ar), 2.38 s (3H,
2
CH3Ar), 3.99 q (2H, CH2CH3, J 7.1), 4.04–4.19 m
(1H, 4-CH), 4.34 d (1H, CH, 2J 12.5), 4.49 d (1H, CH,
2J 13.0), 6.78–6.89 m (3H, Ph), 7.22–7.44 m (3H, Ph),
7.22– 7.44 m (5H, Ph), 9.27 s (1H, NH).
1
The H NMR and 13C spectra were obtained on a
Varian Mercury-300VX spectrometer (75.46 and
300.05 MHz, respectively) at 300 K in a DMSO-d6–
CCl4 mixture (1:3), internal reference TMS. The IR
spectra were recorded on a Specord 75 IR instrument
in mineral oil (thin layer). The melting points were
determined on a Boetius heating block.
2
2
CH, J 12.3), 4.58 d (1H, CH, J 13.1), 6.97–7.14 m
(5H, Ph), 7.24–7.47 m (7H, Ph), 9.43 s (1H, NH). 13C
NMR spectrum, δC, ppm: 13.5 (CH3, OEt), 16.8, 17.0
(CH3), 40.6 (C4), 54.7, 55.1 (C3, C5), 60.3 (CH2);
125.1, 125.2, 125.3, 125.9, 128.0, 128.3, 129.1, 129.4,
129.6, 130.0 (CH, Ar); 132.0, 132.6, 133.9, 135.1,
135.3, 136.2 (Cipso, Ar); 164.4, 166.4, 167.4, 168.2
(C=O).
REFERENCES
1. Sargsyan, M.S., Hayotsyan, S.S., Khachatryan, A.Kh.,
Badasyan, A.E., and Kon'kova, S.G., Khim. Zh. Arm.,
2012, vol. 65, p. 137.
Ethyl 2,6-dioxo-4-(4-nitrophenyl)-1-o-tolyl-5-o-
tolylcarbamoylpiperidine-3-carboxylate (IVc) was
obtained from a mixture of 0.45 g (2 mmol) of amide
Ia and 0.15 g (1 mmol) of aldehyde IIb in 10 ml of
2. Scott, R.W., Neville, S.T., Zhao, L., and Ran, N., WO
Patent 2009/005 647 A2, 2009.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 7 2013