3-acyl-1,2,3,4-tetrahydropyridine-2,4-diones: Synthesis and chemical properties

Article abstract of DOI:10.1134/s1070428008030196

N-Substituted 6-methyl-1,2,3,4-tetrahydropyridine-2,4-diones reacted with aliphatic carboxylic acid chlorides in the presence of pyridine or triethylamine to give the corresponding 4-O-acyl derivatives which underwent O,C-migration of the acyl group by the action of 2 equiv of triethylamine and a catalytic amount of 2-hydroxy-2-methylpropanenitrile. Reactions of 3-acyl-6-methyl-1,2,3,4- tetrahydropyridine-2,4-diones thus formed with aliphatic and aromatic amines gave the corresponding enamino derivatives at the side acyl group. Enamino derivatives at the C⁴ =O group were obtained by transformation of 3-acyl-1,2,3,4-tetrahydropyridine-2,4-diones into 3-acyl-4-methoxy-6-methyl-1,2- dihydropyridin-2-ones via alkylation with dimethyl sulfate and subsequent treatment with amines.

Full text of DOI:10.1134/s1070428008030196

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 3, pp. 432–439. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © D.B. Rubinov, T.A. Zheldakova, I.L. Rubinova, A.V. Baranovskii, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 3, pp. 434–441.
3-Acyl-1,2,3,4-tetrahydropyridine-2,4-diones: Synthesis
and Chemical Properties
D. B. Rubinov, T. A. Zheldakova, I. L. Rubinova, and A. V. Baranovskii
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Akademika Kuprevicha 5/2, Minsk, 220141 Belarus
e-mail: rub_irin@mail.ru
Received May 10, 2006
Abstract—N-Substituted 6-methyl-1,2,3,4-tetrahydropyridine-2,4-diones reacted with aliphatic carboxylic acid
chlorides in the presence of pyridine or triethylamine to give the corresponding 4-O-acyl derivatives which
underwent O,C-migration of the acyl group by the action of 2 equiv of triethylamine and a catalytic amount of
2-hydroxy-2-methylpropanenitrile. Reactions of 3-acyl-6-methyl-1,2,3,4-tetrahydropyridine-2,4-diones thus
formed with aliphatic and aromatic amines gave the corresponding enamino derivatives at the side acyl group.
Enamino derivatives at the C4=O group were obtained by transformation of 3-acyl-1,2,3,4-tetrahydropyridine-
2,4-diones into 3-acyl-4-methoxy-6-methyl-1,2-dihydropyridin-2-ones via alkylation with dimethyl sulfate and
subsequent treatment with amines.
DOI: 10.1134/S1070428008030196
Pyridinone and pyridinedione derivatives are
widely used in the synthesis of natural [1] and biologi-
cally active compounds [2]. 3-Acyl-2,4-dioxopyridine
fragment constitutes a structural base of Tenellin (Ia),
Bassianin (Ib) [3], Militarinone (Ic) [4], Pyridovericin
(Id) [5], and other natural alkaloid pigments isolated
from entomopathogenic fungi. It is known that synthet-
ic 3-aroyl-substituted pyridine-2,4-diones and oximes
derived therefrom (II, Z = NOR′) exhibit herbicidal
activity [6–9]; like carbocyclic β-triketones, they are
prepared from the corresponding pyridinediones via
reaction with aroyl chlorides, followed by O–C migra-
tion of the aroyl group in enol esters in the presence of
potassium cyanide [10, 11]. Syntheses of β-triketones
of the pyrimidine series having an aliphatic side chain
include a number of steps, and the yields of the target
products are often poor [4, 12–14]. Acylation of pyri-
dine-2,4-diones with aliphatic carboxylic acid chlo-
rides was not reported.
We previously proposed a simple and efficient pro-
cedure for the synthesis of 1,6-disubstituted pyridine-
2,4-diones III from 5-(1,3-dioxobutyl)-2,2-dimethyl-
1,3-dioxane-4,6-dione [15]. While continuing studies
on the chemical properties of pyridine-2,4-dione deriv-
atives, we have found that the procedure used by us
previously for the preparation of 2-aroylcyclohexane-
1,3-diones [16] ensures synthesis of 3-acylpyridine-
2,4-diones V in good yields. Our results contradict the
HO
OH
O
O
Z
R2
Rx
Ry
N
O
N
O
R1
R1
Ia–Id
II
I, R1 = OH, R2 =
(a),
(b); R1 = H, R2 =
(c),
H2C
Me
H2C
H2C
Me
Me
Me
Me
Me
Me
Me
H2C
(d); II, R2 = H, Alk, Ar, NH2; Z = O, NOR′ (R′ = Alk, alkenyl, ...); Rx, Ry = Alk, alkenyl, PhO, ...
OH
432

3-ACYL-1,2,3,4-TETRAHYDROPYRIDINE-2,4-DIONES:
433
Scheme 1.
O
OH
N
O
R2
O
O
N
O
O
HO
Me
CN
, Et3N
Me
R2COCl
pyridine or Et3N
R2
Me
O
Me
N
Me
R1
R1
R1
IIIa–IIId
IVa–IVe
Va–Ve
H
H
·
·
·
·
·
·
O
O
O
R2
O
O
O
O
N
R2
R2
O
R2
O
H
H
O
·
·
·
O
Me
N
O
Me
N
Me
N
Me
R1
R1
R1
R1
A
B
C
D
III, R1 = Me (a), Pr (b), PhCH2 (c), 4-MeOC6H4 (d); IV, V, R1 = R2 = Me (a); R1 = Pr, R2 = Et (b); R1 = PhCH2, R2 = Et (c), Me (f);
R1 = 4-MeOC6H4, R2 = Pr (d); R1 = Me, R2 = Bu (e).
data of Schnell and Kappe [11] who failed to obtain
3-aroylpyridine-2,4-diones following an analogous ap-
proach. It should be noted that we did not succeed in
synthesizing β-triketones V using Lewis acids and
4-dimethylaminopyridine as catalysts.
dine-2,4-diones Va–Vf in the presence of excess tri-
ethylamine and 2-hydroxy-2-methylpropanenitrile as
catalyst (Scheme 1).
The assumed structure of enol esters IV follows
1
from the H NMR spectra of compounds IVa–IVc and
Treatment of diketones IIIa–IIId with acetyl, pro-
pionyl, and butyryl chlorides in methylene chloride in
the presence of pyridine gave enol esters IVa–IVf with
high regioselectivity. Compounds IVa–IVf can be iso-
lated as individual substances in 90–95% yield or sub-
jected (without isolation) to O–C-migration of the acyl
group with formation of 3-acyl-1,2,3,4-tetrahydropyri-
IVf, where the 3-H and 5-H olefinic protons (δ 5.50–
6.50 ppm) displayed an allylic coupling constant J of
4
2.0–2.5 Hz. Like other cyclic β-triketones [17], 3-acyl-
pyridine-2,4-diones Va–Vf are completely enolized:
their 1H NMR spectra contain a one-proton signal from
the chelated hydroxy group in the region δ 15–16 ppm.
Theoretically, unsymmetrical heterocyclic β-triketones
Scheme 2.
O
NHR3
R2
R3NH2
Me
N
O
O
N
O
O
R1
R2
VIa–VIh
OMe
O
NHR3
O
O
Me
R1
R2
R2
Me2SO4
R3NH2
Va–Ve
Me
N
O
Me
N
R1
R1
VIIa, VIIb
VIIIa–VIIId
VI, R1 = R2 = Me, R3 = Ph (a), CH2=CHCH2 (b); R1 = Me, R2 = Bu, R3 = CH2=CHCH2 (c), 4-MeOC6H4 (d, h); R1 = Pr, R2 = Et,
R3 = PhCH2 (e); R1 = 4-MeOC6H4, R2 = Pr, R3 = PhCH2 (f), 4-MeOC6H4 (g); R1 = Me, R2 = Bu, R3 = 4-MeOC6H4 (h); VII, R1 = Me,
R2 = Bu (a); R1 = 4-MeOC6H4, R2 = Pr (b); VIII, R1 = 4-MeOC6H4, R2 = Pr, R3 = PhCH2 (a), 4-MeC6H4 (b); R1 = Me, R2 = Bu,
R3 = 4-MeOC6H4 (c), CH2=CHCH2 (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

RUBINOV et al.
434
Va–Vf can give rise to four tautomeric forms A–D.
The presence of only one enol proton signal suggests
that compounds Va–Vf have structure A or C; the con-
tribution of tautomers B and D is quite insignificant, or
they are absent at all.
3-Acylpyridinediones Va–Vf, as well as other cyclic
β-triketones, reacted with amines at the acyl carbonyl
group, yielding enamines VIa–VIh (Scheme 2). The
reactions with aliphatic amines (allylamine and benzyl-
amine) in boiling toluene required several hours,
whereas the conversion of triketones V in the reactions
with aromatic amines (aniline and p-methoxyaniline)
was not complete even after heating for a weak, and
the yields of the corresponding enamines VI did not
exceed 50%.
With a view to extend the synthetic potential of
3-acylpyridine-2,4-diones we tried to obtain their
enamino derivatives at one of the endocyclic carbonyl
groups. Analogous transformations of carbocyclic β-tri-
ketones are usually accomplished via intermediate pre-
paration of the corresponding enol methyl ethers, and
these reactions involve no difficulties [17]. We previ-
ously synthesized regioisomeric enol methyl ethers at
both endocyclic carbonyl groups of sulfur-containing
heterocyclic β-triketones of the 3-acylthiotetronic acid
series [18] and 3-acetyltetrahydrothiopyran-2,4-dione
[19]. 4-Acyl-2H-thiopyran-3,5-diones reacted with
methylating agents to give complex mixtures of prod-
ucts, from which we failed to isolate the desired enol
ethers [20]. By heating triketones Vc and Vf with
1.2 equiv of dimethyl sulfate and 4 equiv of anhydrous
potassium carbonate in toluene we obtained the corre-
sponding 4-methoxy derivatives VIIa and VIIb in
almost quantitative yield. Compounds VIIa and VIIb
reacted with allylamine, benzylamine, aniline, and
p-methoxyaniline to produce enamino derivatives
VIIIa–VIIId at the C4=O carbonyl group. Unlike enol
ethers derived from β-triketones of the cyclohexane
[17] and heterocyclic series [18, 19], 4-methoxypyri-
dinones VIIa and VIIb turned out to be low reactive;
as in the synthesis of enamino derivatives VIa–VIh at
the side-chain carbonyl group, the yields in the reac-
tions of VIIa and VIIb with aromatic amines were
considerably lower.
The product structure was determined using two-
dimensional NMR techniques (COSY, HSQC, HMBC),
and complete assignment of carbon signals in the
13C NMR spectra was made. The assignment of signals
from carbon atoms attached to protons involved no
difficulties, for the COSY and HSQC data were fully
1'''
4'''
Me
Me
O
HN
O
O
O
O
O
N
O
O
4''
Me
Me
4
Me
2''
6
1
N
Me
Me
N
Me
1'
Me
4'
O
O
Me
Me
VIf
VIIa
VIIb
H2C
NH
N
O
O
NH
O
Me
Me
Me
Me
N
O
Me
O
Me
VIIIa
VIIId
Principal 13C–1H interactions in the HMBC spectra of compounds VIf, VIIa, VIIb, VIIIa, and VIIId.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

3-ACYL-1,2,3,4-TETRAHYDROPYRIDINE-2,4-DIONES:
435
consistent with each other. Some problems appeared
while assigning signals from protons in the 4′-meth-
oxyphenyl substituent in compounds Vd, VIf, VIIb,
and VIIIa. The COSY spectra of these compounds
displayed only a weak cross-peak between the methyl
protons and 3′-H. Nevertheless, taking into account
more upfield positions of the 13C (δC 114–115 ppm)
Interactions with protons in the methyl group and
5-H allowed us to distinguish signal from the quater-
nary C6 atom in the pyridine ring. N-Methyl deriva-
tives VIIa and VIIId additionally showed a cross-peak
between C6 and NCH3 protons. Signals from the quat-
ernary carbon atom in the methoxyphenyl substituent
in compounds VIf, VIIb, and VIIIa were assigned on
the basis of coupling between the OCH3 protons and
carbon nucleus resonating at δC 159 ppm; the chemical
shift of the latter was also taken into account.
1
and H signals (δ 6.98–7.03 ppm), they were assigned
to C3′ and 3′-H, respectively, while the signals located
at δC 129–130 ppm and δ 7.07–7.09 ppm were as-
signed to C2′ and 2′-H.
Unlike carbo- [21] and heterocyclic β-triketones
[22, 23] studied previously, we failed to obtain con-
densation products of triketones IIIa and IIIb with
isoquinoline derivatives (diaza analogs of steroids)
regardless of the reaction conditions (acid or base
catalysis).
Signals from quaternary carbon atoms were as-
1
signed by analysis of long-range H–13C couplings in
the HMBC spectra. The principal interactions are
shown in figure. All compounds having an exocyclic
carbonyl group displayed cross-peaks between the
carbonyl carbon atoms (δC 203–208 ppm) and protons
in the α- and β-positions with respect to the carbonyl
group. The corresponding protons in molecule VIf
interact with the carbon nucleus resonating at
δC 179.37 ppm, and that carbon nucleus also gives
a cross-peak with methylene protons in the benzyl
group. These data unambiguously indicate that the
enamino fragment originates from the exocyclic car-
bonyl group. The lactam carbonyl carbon atom (δC 162–
165 ppm) showed no strong cross-peaks because of the
absence of protons in the vicinity of C2=O. Only the
HMBC spectra of N-methyl derivatives VIIa and
VIIId contained cross peaks resulting from coupling
between the methyl protons and the carbonyl carbon
atom. The quaternary carbon atom in the 3-position of
the pyridine ring is readily identified taking into
account upfield position of the corresponding signal
(δC 101–112 ppm) and the presence of a cross-peak
due to coupling with 5-H. Enamines VIIIa and VIIId
also displayed a cross-peak between C3 and NH pro-
ton. It should be noted that the C3 signal in the spectra
of methyl ethers VIIa and VIIb is observed in
a weaker field as compared to the other examined com-
pounds (ΔδC ≈ 10 ppm).
The C4 signal was identified by the presence of
a weak cross peak with 5-H and (for 4-substituted
compounds) by the coupling with protons of the meth-
oxy group (VIIa, VIIb) and methylene protons in the
secondary amine moiety (VIIIa, VIIId). Here, varia-
tions of 13C chemical shifts reflect the character of
substitution and degree of conjugation in the system.
The C4 signal in the spectra of enamino derivatives
appears at δC 159 ppm, methoxy compounds display
the C4 signal in a weaker field (by 5–6 ppm), while the
C4 nucleus in diketone VIf resonates at δC 183.73 ppm.
EXPERIMENTAL
The IR spectra of solid products were recorded in
KBr on a UR-20 spectrometer; liquid products were
examined as films (neat). The 1H and 13C NMR spectra
were measured on a Bruker Avance 500 instrument at
500 and 125 MHz, respectively; chloroform-d was
used as solvent, and tetramethylsilane, as reference.
The mass spectra were run on an MKh-1320 spectrom-
eter. The melting points were determined on a Boetius
hot stage. The progress of reactions and the purity of
products were monitored by thin-layer chromatog-
raphy on Silufol UV-254 or Alufol UV-254 plates
(Merck); spots were detected under UV light, followed
by spraying with a solution of iron(III) chloride.
Preparative thin-layer chromatography was performed
using silica gel Kieselgel 60 HF254 (Merck).
Enol esters IVa–IVd (general procedure). Pyri-
dine, 10.5 ml (0.13 mol), and the corresponding car-
boxylic acid chloride, 0.11 mol, were added under stir-
ring to a mixture of 0.1 mol of diketone IIIa–IIId and
100 ml of methylene chloride. The mixture was stirred
for 24 h at room temperature (TLC), 50 ml of cold
water was added, the mixture was acidified to pH 5 by
adding 2 N hydrochloric acid, the organic phase was
separated, washed with water and a 5% solution of
sodium carbonate, and dried over magnesium sulfate,
and the solvent was removed on a rotary evaporator.
1,6-Dimethyl-2-oxo-1,2-dihydropyridin-4-yl
acetate (IVa). Yield 95%, mp 136–137°C (from di-
ethyl ether). IR spectrum, ν, cm–1: 1775, 1670, 1600,
1
1570. H NMR spectrum, δ, ppm: 2.27 s (3H, 6-CH3),
2.36 s (3H, CH3CO), 3.50 s (3H, NCH3), 5.96 d (1H,
5-H, J = 2.5 Hz), 6.23 d (1H, 3-H, J = 2.5 Hz). Found,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

RUBINOV et al.
436
%: C 59.80; H 6.21; N 7.87. [M]+ 181. C9H11NO3. Cal-
culated, %: C 59.66; H 6.12; N 7.73. M 181.19.
spectrum, cm–1: 1655 (C=O, lactam), 1615 (CH3C=O),
1580 (C=C, enol). H NMR spectrum, δ, ppm: 2.36 s
1
(3H, 6-CH3), 2.74 s (3H, COCH3), 3.45 s (3H, CH3N),
5.86 s (1H, 5-H), 15.52 s (1H, OH). Found, %: C 59.59;
H 6.07; N 7.84. [M]+ 181. C9H11NO3. Calculated, %:
C 59.66; H 6.12; N 7.73. M 181.19.
6-Methyl-2-oxo-1-propyl-1,2-dihydropyridin-4-
yl propanoate (IVb). Yield 90%. Oily substance. IR
1
spectrum, ν, cm–1: 1780, 1670, 1600, 1570. H NMR
spectrum, δ, ppm: 0.98 t (3H, CH3CH2CH2, J =
7.0 Hz), 1.23 t (3H, CH3CH2CO, J = 7.5 Hz), 1.72 m
(2H, CH3CH2CH2), 2.38 s (3H, 6-CH3), 2.54 q (2H,
CH3CH2CO, J = 7.5 Hz), 3.96 m (2H, NCH2), 5.94 d
(1H, 5-H, J = 2.5 Hz), 6.20 d (1H, 3-H, J = 2.5 Hz).
Found, %: C 64.60; H 7.83; N 6.43. [M]+ 223.
C12H17NO3. Calculated, %: C 64.55; H 7.67; N 6.27.
M 223.27.
6-Methyl-1-propyl-3-propionyl-1,2,3,4-pyridine-
2,4-dione (Vb). Yield 85%, mp 58–59°C. IR spectrum,
ν, cm–1: 1665 (C=O, lactam), 1620 (EtC=O), 1570
1
(C=C, enol). H NMR spectrum, δ, ppm: 0.99 t (3H,
CH3CH2CH2, J = 7.4 Hz), 1.16 t (3H, CH3CH2CO,
J = 7.4 Hz), 1.69 m (2H, CH3CH2CH2), 2.37 s (3H,
6-CH3), 3.18 q (2H, CH3CH2CO, J = 7.0 Hz), 3.87 m
(2H, NCH2), 5.81 s (1H, 5-H), 15.60 s (1H, OH).
Found, %: C 64.47; H 7.50; N 6.37. [M]+ 223.
C12H17NO3. Calculated, %: C 64.55; H 7.67; N 6.27.
M 223.27.
1-Benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-
yl propanoate (IVc). Yield 93%, mp 86–87°C. IR
1
spectrum, ν, cm–1: 1765, 1660, 1600, 1580. H NMR
spectrum, δ, ppm: 1.25 t (3H, CH3CH2, J = 7.5 Hz),
2.28 s (1H, 6-CH3), 2.58 q (2H, CH3CH2, J = 7.5 Hz),
5.34 s (2H, CH2C6H5), 5.95 d (1H, 5-H, J = 2.5 Hz),
6.33 d (1H, 3-H, J = 2.5 Hz), 7.13–7.37 m (5H, C6H5).
Found, %: C 70.96; H 6.51; N 5.20. [M]+ 271.
C16H17NO3. Calculated, %: C 70.83; H 6.32; N 5.16.
M 271.32.
1-Benzyl-6-methyl-3-propionyl-1,2,3,4-tetrahy-
dropyridine-2,4-dione (Vc). Yield 80%, mp 75–76°C.
IR spectrum, ν, cm–1: 1670 (C=O, lactam), 1625
1
(EtC=O), 1570 (C=C, enol). H NMR spectrum, δ,
ppm: 1.60 t (3H, CH3CH2, J = 7.0 Hz), 2.28 s (3H,
6-CH3), 3.21 q (2H, CH3CH2), 5.27 s (2H, CH2C6H5),
5.86 s (1H, 5-H), 7.13 d (2H, Harom), 7.26 m (1H,
Harom), 7.33 m (2H, Harom), 15.74 s (1H, OH). Found,
%: C 70.89; H 6.33; N 5.22. [M]+ 271. C16H17NO3.
Calculated, %: C 70.83; H 6.32; N 5.16. M 271.32.
1-(4-Methoxyphenyl)-6-methyl-2-oxo-1,2-dihydro-
pyridin-4-yl butanoate (IVd). Yield 97%, mp 109–
110°C. IR spectrum, ν, cm–1: 1780, 1670, 1610, 1570.
1H NMR spectrum, δ, ppm: 1.04 t (3H, CH3CH2, J =
7.7 Hz), 1.77 m (2H, CH3CH2), 1.97 s (3H, 6-CH3),
2.53 t (2H, CH2CH2, J = 7.3 Hz), 3.85 s (3H, OCH3),
6.00 d (1H, 5-H, J = 2.2 Hz), 6.28 d (1H, 3-H, J =
2.2 Hz), 7.03 d (2H, C6H4, J = 8.8 Hz), 7.10 d (2H,
C6H4, J = 8.8 Hz). Found, %: C 67.69; H 6.47; N 4.48.
[M]+ 301. C17H19NO4. Calculated, %: C 67.76; H 6.36;
N 4.65. M 301.34.
3-Butyryl-1-(4-methoxyphenyl)-6-methyl-1,2,3,4-
tetrahydropyridine-2,4-dione (Vd). Yield 82%,
mp 105–106°C. IR spectrum, ν, cm–1: 1670 (C=O,
lactam); 1620 (PrC=O); 1610, 1570 (C=C, enol).
1H NMR spectrum, δ, ppm: 0.94 t (3H, CH3CH2, J =
7.4 Hz), 1.66 m (2H, CH3CH2), 1.99 s (3H, CH3CH2),
2.28 s (3H, CH3C=CH), 3.11 t (2H, CH2CH2, J =
7.4 Hz), 3.85 s (3H, OCH3), 5.93 s (1H, 5-H), 7.03 m
(2H, Harom), 7.08 m (2H, Harom), 15.97 s (1H, OH).
13C NMR spectrum, δC, ppm: 13.82 (C4″), 17.36 (C3″),
22.33 (6-Me), 44.71 (C2″), 55.54 (MeO), 100.90 (C5),
105.43 (C3), 115.12 (C3′), 129.08 (C2′), 130.60 (C1′),
154.08 (C6), 159.72 (C4′), 163.50 (C2), 176.30 (C4),
208.30 (C1″). Found, %: C 67.89; H 6.32; N 4.72.
[M]+ 301. C17H19NO4. Calculated, %: C 67.76; H 6.36;
N 4.65. M 301.34.
3-Acyl-6-methyl-1,2,3,4-tetrahydropyridine-2,4-
diones Va–Vd (general procedure). Compound IVa–
IVd, 0.05 mol, was dissolved in 50 ml of methylene
chloride, 14 ml (0.1 mol) of triethylamine and 0.5 ml
(0.005 mol) of 2-hydroxy-2-methypropanenitrile were
adde, and the mixture was stirred for 48 h at 25–30°C,
following the disappearance of initial compound IVa–
IVd (TLC). The mixture was acidified to pH 5 with
10% hydrochloric acid, and the organic phase was
separated, washed with water, dried over magnesium
sulfate, and passed through a thin layer of silica gel.
The solvent was removed under reduced pressure on
a rotary evaporator, and the oily residue was recrystal-
lized from ethyl acetate–petroleum ether.
3-Acyl-6-methyl-1,2,3,4-tetrahydropyridine-2,4-
diones Ve and Vf (general procedure). Triethylamine,
18.2 ml (0.13 mol), was added under stirring to a mix-
ture of 0.1 mol of diketone IIIa or IIIc in 100 ml of
methylene chloride, and a solution of 0.11 mol of pen-
tanoyl or acetyl chloride in methylene chloride (1:1 by
volume) was added dropwise over a period of 4 h
under stirring. The mixture was then stirred for 0.5 h at
3-Acetyl-1,6-dimethyl-1,2,3,4-tetrahydropyri-
dine-2,4-dione (Va). Yield 83%, mp 130–131°C. IR
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3-ACYL-1,2,3,4-TETRAHYDROPYRIDINE-2,4-DIONES:
437
room temperature, and 28 ml (0.20 mol) of triethyl-
amine and 0.5 ml (0.005 mol) of 2-hydroxy-2-methyl-
propanenitrile were added. As in the reactions with
enol esters IV, the C–O isomerization was complete
in 48 h (TLC). The mixture was treated as described
above.
85%, mp 69–69.5°C (from diethyl ether). IR spectrum,
ν, cm–1: 3070, 1660, 1620, 1600, 1560. 1H NMR spec-
trum, δ, ppm: 2.22 s (3H, 6-CH3), 2.70 s (2H, CH3CN),
3.35 s (3H, CH3N), 4.13 t (2H, NHCH2, J = 5.5 Hz),
5.29 m (2H, CH2=CH), 5.70 s (1H, 5-H), 5.90 m
(1H, CH2=CH), 15.3 s (1H, NH). Found, %: C 65.61;
H 7.42; N 12.66. [M]+ 220. C12H16N2O2. Calculated,
%: C 65.43; H 7.32; N 12.72. M 220.27.
1,6-Dimethyl-3-pentanoyl-1,2,3,4-tetrahydropyr-
idine-2,4-dione (Ve). Yield 73%. Oily substance. IR
spectrum, ν, cm–1: 1660 (C=O, lactam), 1620 (BuC=O),
3-[1-(2-Allylamino)pentylidene]-1,6-dimethyl-
1,2,3,4-tetrahydropyridine-2,4-dione (VIc). Yield
87%, mp 38–40°C (from diethyl ether). IR spectrum,
ν, cm–1: 3070, 1655, 1620, 1590, 1560. 1H NMR spec-
trum, δ, ppm: 0.97 t (3H, CH3CH2, J = 7.4 Hz), 1.51 m
(2H, CH2CH3), 2.22 s (3H, 6-CH3), 3.13 m (2H,
CH2CH2CH2), 3.35 s (3H, CH3N), 4.13 t (2H, NHCH2,
J = 5.5 Hz), 5.30 m (2H, CH2=CH), 5.67 s (1H, 5- H),
5.90 m (1H, CH2=CH), 15.3 s (1H, NH). Found, %:
C 68.77; H 8.55; N 10.46. [M]+ 262. C15H22N2O2. Cal-
culated, %: C 68.67; H 8.45; N 10.68. M 262.35.
1
1565 (C=C, enol). H NMR spectrum, δ, ppm: 0.95 t
(3H, CH3CH2CH2, J = 7.3 Hz), 1.41 m (2H, CH3CH2-
CH2), 1.65 m (2H, CH2CH2CH2), 2.35 s (3H, 6-CH3),
3.17 t (2H, CH2CH2CO, J = 7.7 Hz), 3.45 s (3H,
NCH3), 5.84 s (1H, 5-H), 15.67 s (1H, OH). Found, %:
C 64.69; H 7.65; N 6.40. [M]+ 223. C12H17NO3. Cal-
culated, %: C 64.55; H 7.67; N 6.27. M 223.27.
3-Acetyl-1-benzyl-6-methyl-1,2,3,4-tetrahydro-
pyridine-2,4-dione (Vf). Yield 75%. Oily substance.
IR spectrum, ν, cm–1: 1660 (C=O, lactam), 1620
1
(MeC=O), 1575 (C=C, enol). H NMR spectrum, δ,
3-{1-[(4-Methoxyphenyl)amino]propylidene}-6-
methyl-1-propyl-1,2,3,4-tetrahydropyridine-2,4-di-
one (VId). Yield 44%, mp 89–90°C (from diethyl
ether). IR spectrum, ν, cm–1: 3080, 1670, 1620, 1590,
ppm: 2.28 s (3H, 6-CH3), 2.74 s (3H, CH3CO), 5.27 s
(2H, CH2C6H5), 5.86 s (1H, 5-H), 7.13 d (2H, Harom),
7.27 m (1H, Harom), 7.33 m (2H, Harom), 15.65 s (1H,
OH). Found, %: C 70.13; H 5.78; N 5.42. [M]+ 257.
C15H15NO3. Calculated, %: C 70.02; H 5.88; N 5.44.
M 257.19.
1
1560. H NMR spectrum, δ, ppm: 1.00 t (3H,
CH3CH2CH2, J = 7.5 Hz), 1.22 t (3H, NHCCH2CH3,
J = 7.5 Hz), 1.68 m (2H, CH3CH2CH2), 2.30 s (3H,
6-CH3), 3.10 q (2H, NHCCH2CH3, J = 7.5 Hz), 3.80 m
(2H, NCH2), 3.84 s (3H, OCH3), 5.73 s (1H, 5-H),
6.94 d (2H, C6H4, J = 9.0 Hz), 7.12 d (2H, C6H4, J =
9.0 Hz), 16.85 s (1H, NH). Found, %: C 69.77; H 7.61;
N 8.37. [M]+ 328. C19H24N2O3. Calculated, %: C 69.49;
H 7.37; N 8.53. M 328.41.
Enamines VIa–VIh (general procedure). Triketone
Va, Vb, Vd, or Ve, 5 mmol, was dissolved in 50 ml of
toluene, 6.5 mmol of the corresponding amine was
added, and the mixture was heated under reflux for 4–6
(aliphatic amines) or 60 h (aromatic amines), the prog-
ress of the reaction being monitored by TLC. The mix-
ture was washed with 5% hydrochloric acid and water,
the aqueous phases were combined and extracted with
chloroform (3×10 ml), the chloroform extracts were
combined with the toluene layer, dried over anhydrous
magnesium sulfate, and passed through a thin layer
of silica gel, and the solvent was evaporated under
reduced pressure.
3-[1-(Benzylamino)propylidene]-6-methyl-1-
propyl-1,2,3,4-tetrahydropyridine-2,4-dione (VIe).
Yield 82%. Oily substance. IR spectrum, ν, cm–1:
1
3080, 1670, 1620, 1590, 1560. H, δ, ppm: 0.95 t (3H,
CH3CH2CH2, J = 7.5 Hz), 1.23 t (3H, NHCCH2CH3,
J = 7.5 Hz), 1.68 m (2H, CH3CH2CH2), 2.23 s (3H,
6-CH3), 3.24 q (2H, NHCCH2CH3, J = 7.5 Hz), 3.82 m
(2H, NCH2), 4.78 d (2H, NHCH2Ph, J = 5.5 Hz),
5.68 s (1H, 5-H), 7.20–7.42 m (5H, C6H5), 15.65 s
(1H, NH). Found, %: C 73.10; H 7.65; N 9.01.
[M]+ 312. C19H24N2O2. Calculated, %: C 73.05; H 7.74;
N 8.97. M 312.41.
1,6-Dimethyl-3-[1-(phenylamino)ethylidene]-
1,2,3,4-tetrahydropyridine-2,4-dione (VIa). Yield
52%, mp 116–118°C (from diethyl ether). IR spectrum,
ν, cm–1: 3060, 1660, 1620, 1560. 1H NMR spectrum, δ,
ppm: 2.25 s (3H, 6-CH3), 2.71 s (3H, CH3CN), 3.42 s
(3H, CH3N), 5.79 s (1H, 5-H), 7.10–7.40 m (5H,
C6H5), 17.1 s (1H, NH). Found, %: C 70.39; H 6.21;
N 11.02. [M]+ 256. C15H16N2O2. Calculated, %:
C 70.29; H 6.29; N 10.93. M 256.30.
3-[1-(Benzylamino)butylidene]-6-methyl-1-(4-
methoxyphenyl)-1,2,3,4-tetrahydropyridine-2,4-di-
one (VIf). Yield 85%, mp 154–155°C (from ethyl
acetate). IR spectrum, ν, cm–1: 3080, 1670, 1630, 1590,
1
3-[1-(2-Allylamino)ethylidene]-1,6-dimethyl-
1560. H NMR spectrum, δ, ppm: 1.00 t (3H,
1,2,3,4-tetrahydropyridine-2,4-dione (VIb). Yield
CH3CH2CH2, J = 7.4 Hz), 1.64 m (4H, CH3CH2CH2),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

RUBINOV et al.
438
1.82 s (3H, 6-CH3), 3.13 t (1.6H, J = 8.0 Hz) and
3.31 br.s (0.4H, NHCCH2CH2), 3.83 s (3H, OCH3),
4.64 br.s (0.4H) and 4.71 d (1.6H, J = 5.5 Hz)
(NHCH2Ph), 5.74 s (1H, 5-H), 6.97 m (2H, Harom),
7.08 m (2H, Harom), 7.33–7.38 m (5H, Harom), 15.59 s
(1H, NH). Found, %: C 73.98; H 6.65; N 7.03.
[M]+ 390. C24H26N2O3. Calculated, %: C 73.82; H 6.71;
N 7.17. M 390.48.
4-Methoxy-1,6-dimethyl-3-pentanoyl-1,2-dihy-
dropyridin-2-one (VIIa). Yield 98%, mp 52–53°C. IR
1
spectrum, ν, cm–1: 1700, 1655, 1590, 1560. H NMR
spectrum, δ, ppm: 0.90 t (3H, CH3CH2CH2, J =
7.4 Hz), 1.35 m (2H, CH3CH2CH2), 1.64 m (2H, CH2-
CH2CH2), 2.39 s (3H, 6-CH3), 2.83 t (2H, CH2CH2CO,
J = 7.7 Hz), 3.48 s (3H, NCH3), 3.82 s (3H, OCH3),
13
5.95 s (1H, 5-H). C NMR spectrum, δC, ppm: 13.97
(C5″), 21.74 (6-Me), 22.41 (C4″), 26.11 (C3″), 30.82
(C1′), 43.54 (C2″), 56.02 (MeO), 94.84 (C5), 112.64
(C3), 127.16 (C2′′′), 149.25 (C6), 162.03 (C2), 164.08
(C4), 203.18 (C1″). Found, %: C 65.64; H 7.95; N 6.02.
[M]+ 237. C13H19NO3. Calculated, %: C 65.80; H 8.07;
N 5.90. M 237.30.
1-(4-Methoxyphenyl)-6-methyl-3-[1-(4-tolyl-
amino)butylidene]-1,2,3,4-tetrahydropyridine-2,4-
dione (VIg). Yield 44%, mp 150–152°C (from diethyl
ether). IR spectrum, ν, cm–1: 3060, 1660, 1625, 1560,
1
1520. H NMR spectrum, δ, ppm: 0.80 t (2.4H, J =
7.4 Hz) and 0.89–0.98 m (0.6H) (CH3CH2CH2),
1.60 m (2H, CH3CH2CH2), 1.86 s (3H, 6-CH3), 2.39 s
(CH3C6H4), 2.98 t (1.6H, J = 7.7 Hz) and 3.14 m
(0.4H) (CH2CH2CH3), 3.84 s (3H, CH3O), 5.81 s (1H,
5-H), 6.97–7.25 m (8H, Harom), 14.7 s (0.2H) and
16.85 s (0.8H) (NH). 13C NMR spectrum, δC, ppm:
14.60 (C4″), 20.86 (C3″), 21.81 (6-Me), 31.95 (C2″),
47.20 (CH2Ph), 55.44 (MeO), 101.92 (C3), 107.50
(C5), 114.76 (C3′), 127.16 (C2′′′), 127.96 (C4′′′), 129.03
(C3′′′), 129.76 (C2′), 131.87 (C1′), 136.04 (C1′′′), 149.12
(C6), 159.17 (C4′), 165.03 (C2), 183.73 (C4), 179.37
(C1″). Found, %: C 74.01; H 6.61; N 7.30. [M]+ 390.
C24H26N2O3. Calculated, %: C 73.82; H 6.71; N 7.17.
M 390.48.
3-Butanoyl-4-methoxy-1-(4-methoxyphenyl)-6-
methyl-1,2-dihydropyridin-2-one (VIIb). Yield 97%,
mp 142–143°C. IR spectrum, ν, cm–1: 1710, 1650,
1
1610, 1585. H NMR spectrum, δ, ppm: 0.92 t (3H,
CH3CH2CH2, J = 7.4 Hz), 1.67 m (2H, CH3CH2CH2),
2.03 s (3H, 6-CH3), 2.85 t (2H, CH2CH2CO, J =
7.4 Hz), 3.84 s (3H, NCH3), 3.88 s (3H, OCH3), 6.02 s
(1H, 5-H), 7.08 m (2H, Harom), 7.14 m (2H, Harom).
13C NMR spectrum, δC, ppm: 13.93 (C4″), 17.58 (C3″),
22.50 (6-Me), 45.75 (C2″), 55.67 (4′-MeO), 56.36
(4-MeO), 94.95 (C5), 113.05 (C3), 115.18 (C3′), 129.06
(C2′), 130.70 (C1′), 150.09 (C6), 159.81 (C4′), 162.84
(C2), 165.30 (C4), 202.96 (C1″). Found, %: C 65.64;
H 7.95; N 6.02. [M]+ 315. C18H21NO4. Calculated, %:
C 68.55; H 6.71; N 4.44. M 315.37.
1,6-Dimethyl-3-[1-(4-methoxyphenylamino)-
pentylidene]-1,2,3,4-tetrahydropyridine-2,4-dione
(VIh). Yield 48%, mp 120–121°C (from methanol). IR
spectrum, ν, cm–1: 3050, 1650, 1625, 1570, 1555.
1H NMR spectrum, δ, ppm: 0.79 t (3H, CH3CH2CH2,
J = 7.1 Hz), 1.29 m (2H, CH3CH2CH2), 1.56 m (2H,
CH3CH2CH2), 2.26 s (3H, 6-CH3), 3.05 m (2H, NH-
CCH2CH2), 3.80 s (3H, NCH3), 3.84 s (3H, CH3O),
5.74 s (1H, 5-H), 6.93 m (2H, Harom), 7.08 m (2H,
Harom), 16.85 s (1H, NH). Found, %: C 69.33; H 7.17;
N 8.47. [M]+ 328. C19H24N2O3. Calculated, %: C 69.49;
H 7.37; N 8.53. M 328.41.
Enamines VIIIa–VIIId (general procedure).
A mixture of 0.01 mol of 4-methoxypyridine VIIa or
VIIb and 0.013 mmol of the corresponding amine in
50 ml of toluene was heated for 18–24 h under reflux
(TLC). The mixture was then treated as described
above for enamino derivatives VI.
4-Benzylamino-3-butanoyl-1-(4-methoxy-
phenyl)-6-methyl-1,2-dihydropyridin-2-one (VIIIa).
Yield 85%, mp 145–146°C (from methanol). IR spec-
trum, ν, cm–1: 3070, 1660, 1630, 1560, 1520. 1H NMR
spectrum, δ, ppm: 0.92 t (3H, CH3CH2CH2, J =
7.4 Hz), 1.63 m (2H, CH3CH2CH2), 1.87 s (3H,
6-CH3), 3.10 t (2H, CH2CH2CO, J = 7.4 Hz), 3.83 s
(3H, OCH3), 4.52 d (2H, NHCH2, J = 5.8 Hz), 5.73 s
(1H, 5-H), 6.99 m (2H, Harom), 7.07 m (2H, Harom),
7.26–7.40 m (5H, Harom), 11.53 t (1H, NH, J =
5.45 Hz). 13C NMR spectrum, δC, ppm: 14.12 (C4″),
18.15 (C3″), 22.58 (6-Me), 46.31 (C2″), 46.64 (CH2Ph),
55.56 (4′-MeO), 94.48 (C5), 101.73 (C3), 114.95 (C3′),
127.05 (C2′′′, C6′′′), 127.66 (C4′′′), 128.98 (C3′′′, C5′′′),
129.46 (C2′), 131.48 (C1′), 150.80 (C6), 137.41 (C1′′′),
159.45 (C4′), 164.52 (C2), 159.82 (C4), 204.82 (C1″).
Enol ethers VIIa and VIIb (general procedure).
Triketone Vd or Ve, 0.05 mol, was dissolved in 50 ml
of toluene, 2.8 g (0.02 mol) of finely powdered anhy-
drous potassium carbonate and 0.57 ml (0.06 mol) of
dimethyl sulfate were added, and the mixture was
heated for 6–8 h under reflux with stirring. The mix-
ture was cooled and filtered from potassium carbonate,
the precipitate was washed on a filter with toluene, the
filtrate was passed through a thin layer of silica gel, the
solvent was removed under reduced pressure, and the
residue was recrystallized from a mixture of diethyl
ether and petroleum ether.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

3-ACYL-1,2,3,4-TETRAHYDROPYRIDINE-2,4-DIONES:
439
Found, %: C 73.78; H 6.60; N 7.25. [M]+ 390.
C24H26N2O3. Calculated, %: C 73.82; H 6.71; N 7.17.
M 390.48.
3. Wat, C.-K., McInnes, A.G., Smith, D.G., Wright, J.L.C.,
and Vining, L.C., Can. J. Chem., 1977, vol. 55, p. 4090.
4. Schmidt, K., Riese, U., Li, Z., and Hamburger, M.,
J. Nat. Prod., 2003, vol. 66, p. 378.
3-Butanoyl-1-(4-methoxyphenyl)-6-methyl-4-(4-
tolylamino)-1,2-dihydropyridin-2-one (VIIIb). Yield
43%, mp 153–154°C (from diethyl ether). IR spec-
trum, ν, cm–1: 3070, 1665, 1630, 1560, 1520. 1H NMR
spectrum, δ, ppm: 0.95 t (3H, CH3CH2CH2, J =
7.4 Hz), 1.67 m (2H, CH3CH2), 1.83 s (3H, CH3C6H4),
2.38 s (3H, 6-CH3), 3.15 t (2H, CH2CH2CO, J =
7.7 Hz), 3.84 s (3H, NCH3), 5.87 s (1H, 5-H), 7.01 m
(2H, Harom), 7.09 m (2H, Harom), 7.14 m (2H, Harom),
7.21 m (2H, Harom), 12.63 s (1H, NH). Found, %:
C 73.98; H 6.65; N 7.03. [M]+ 390. C24H26N2O3. Cal-
culated, %: C 73.82; H 6.71; N 7.17. M 390.48.
5. Irlapati, N.G., Adlington, R.M., Conte, A., Prit-
chard, G.J., Marquez, R., and Baldwin, J.E., Tetra-
hedron, 2004, vol. 60, p. 9307.
6. Hirono, Y., Ishikawa, H., Iwataki, I., and Sawaki, M.,
JPN Patent Appl. no. 75-154272, 1975; Chem. Abstr.,
1976, vol. 85, no. 78010s.
7. Grina, J., FRG Patent Appl. no. 3820538, 1989; Chem.
Abstr., 1989, vol. 110, no. 212625x.
8. Curtis, J.K., EPV Patent Appl. no. 249149, 1987; Chem.
Abstr., 1988, vol. 109, no. 73334r.
9. Geach, N.J., Gilmour, J., Hatton, L.R., and
Smith, P.H.G., EPV Patent Appl. no. 278742, 1988;
Chem. Abstr., 1989, vol. 110, no. 38898b.
4-(4-Methoxyphenylamino)-1,6-dimethyl-3-pen-
tanoyl-1,2-dihydropyridin-2-one (VIIIc). Yield 45%,
mp 98–99°C (from hexane). IR spectrum, ν, cm–1:
10. Kappe, T. and Schnell, B., J. Heterocycl. Chem., 1996,
vol. 33, p. 663.
1
11. Schnell, B. and Kappe, T., Monatsh. Chem., 1998,
vol. 129, p. 871.
12. Alonso, P., Martin-Leon, N., Quinteiro, M., and
3050, 1650, 1620, 1565, 1520. H NMR spectrum, δ,
ppm: 0.96 t (3H, CH3CH2CH2, J = 7.4 Hz), 1.42 m
(2H, CH3CH2CH2), 1.67 m (2H, CH3CH2CH2), 2.19 s
(3H, 6-CH3), 3.20 t (2H, CH2CH2CO, J = 7.4 Hz),
3.41 s (3H, NCH3), 3.83 s (3H, OCH3), 5.69 s (1H,
5-H), 6.91 m (2H, Harom), 7.10 m (2H, Harom), 12.26 s
(1H, NH). Found, %: C 69.48; H 7.27; N 8.35.
[M]+ 328. C19H24N2O3. Calculated, %: C 69.49; H 7.37;
N 8.53. M 328.41.
Soto, J.L., Justus Liebigs Ann. Chem., 1990, p. 841.
13. Takahashi, S., Kakinuma, N., Uchida, K., Hashimo-
to, R., Yanagishima, T., and Nakagawa, A., J. Antibiot.,
1998, vol. 51, p. 596.
14. Kappe, T. and Kappe, C.O., J. Heterocycl. Chem., 1989,
vol. 26, p. 1555.
15. Rubinov, D.B., Zheldakova, T.A., and Rubinova, I.L.,
Russ. J. Org. Chem., 2004, vol. 40, p. 1329.
16. Rubinov, D.B., Rubinova, I.L., and Akhrem, A.A., Russ.
J. Org. Chem., 1995, vol. 31, p. 386.
4-Allylamino-1,6-dimethyl-3-pentanoyl-1,2-dihy-
dropyridin-2-one (VIIId). Yield 65%, mp 59–60°C
(from diethyl ether). IR spectrum, ν, cm–1: 3090, 1660,
1
1620, 1570, 1520. H NMR spectrum, δ, ppm: 0.94 t
17. Rubinov, D.B., Rubinova, I.L., and Akhrem, A.A.,
(3H, CH3CH2CH2, J = 7.4 Hz), 1.39 m (2H, CH3CH2-
CH2), 1.63 m (2H, CH3CH2CH2), 2.29 s (3H, 6-CH3),
3.14 t (2H, CH2CH2CO, J = 7.69 Hz), 3.41 s (3H,
NCH3), 3.88 m (2H, NHCH2), 5.23 m (2H, CH2=CH),
5.62 s (1H, 5-H), 5.88 m (1H, CH2=CH), 10.90 s (1H,
Chem. Rev., 1999, vol. 99, p. 1047.
18. Budnikova, M.V. and Rubinov, D.B., Russ. J. Org.
Chem., 2001, vol. 37, p. 1478.
19. Budnikova, M.V., Gulyakevich, O.V., Zheldakova, T.A.,
Mikhal’chuk, A.L., and Rubinov, D.B., Russ. J. Org.
Chem., 2002, vol. 38, p. 1696.
20. Zheldakova, T.A., Budnikova, M.V., Rubinova, I.L., and
Rubinov, D.B., Russ. J. Org. Chem., 2003, vol. 39,
p. 1772.
21. Gulyakevich, O.V., Mikhal’chuk, A.L., Verenich, A.I.,
Rubinov, D.B., Zenyuk, A.A., and Akhrem, A.A.,
Enaminy v organicheskom sinteze (Enamines in Organic
Synthesis), Yekaterinburg: Ural. Otd. Ross. Akad. Nauk,
1996, p. 111.
13
NH). C NMR spectrum, δC, ppm: 14.30 (C5″), 22.03
(6-Me), 22.83 (C4″), 27.33 (C3″), 30.52 (C1′), 44.10
(C2″), 44.85 (C1′′′), 94.56 (C5), 101.74 (C3), 133.33
(C2′′′), 116.89 (C3′′′), 150.15 (C6), 164.06 (C2), 159.01
(C4), 205.01 (C1″). Found, %: C 68.77; H 8.55;
N 10.46. [M]+ 262. C15H22N2O2. Calculated, %:
C 68.67; H 8.45; N 10.68. M 262.35.
REFERENCES
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chuk, A.L., Khim. Geterotsikl. Soedin., 2002, p. 1067.
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