Synthesis of 1,6-disubstituted 2,4-pyridinediones from 5-acetoacetyl-2,2- dimethyl-1,3-dioxane-4,6-dione

Article abstract of DOI:10.1007/s11178-005-0015-3

5-Acetoacetyl-2,2-dimethyl-1,3-dioxane-4,6-dione reacts with aliphatic amines and p-methoxy-aniline to afford the corresponding 5-[3-alkyl(or aryl)amino-2-butenoyl] derivatives. Heating of the latter in boiling toluene gives 86-90% of N-substituted 6-meth

Full text of DOI:10.1007/s11178-005-0015-3

Russian Journal of Organic Chemistry, Vol. 40, No. 9, 2004, pp. 1329–1331. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 9, 2004,
pp. 1376–1378.
Original Russian Text Copyright © 2004 by Rubinov, Zheldakova, Rubinova.
Synthesis of 1,6-Disubstituted 2,4-Pyridinediones
from 5-Acetoacetyl-2,2-dimethyl-1,3-dioxane-4,6-dione
D. B. Rubinov, T. A. Zheldakova, and I. L. Rubinova
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Akademika Kuprevicha 5/2, Minsk, 220141 Belarus
e-mail: rubinov@iboch.bas-net.by
Received April 15, 2004
Abstract—5-Acetoacetyl-2,2-dimethyl-1,3-dioxane-4,6-dione reacts with aliphatic amines and p-methoxy-
aniline to afford the corresponding 5-[3-alkyl(or aryl)amino-2-butenoyl] derivatives. Heating of the latter in
boiling toluene gives 86–90% of N-substituted 6-methylpyridine-3-carboxylic acids which undergo decar-
boxylation in diethylene glycol dimethyl ether at 160°C, leading to N-substituted 6-methyl-1,2,3,4-tetrahydro-
pyridine-2,4-diones in high yields.
1
presence in the H NMR spectra of compounds IVa–
IVd of two sharp one-proton singlets at δ 9–10 and
15–16 ppm indicates that they exist as the enamino
tautomer in which both enol proton and proton on the
nitrogen atom are involved in intramolecular hydrogen
bonds (H-chelate rings).
Polyketones I, which are readily available from
Meldrum’s acid, are convenient synthons for the
preparation of 6-substituted 2,4-pyrandiones III via
decarboxylation of acid II [1, 2]. While developing
synthetic approaches to heterocyclic β-triketones
[3, 4], we used 5-acetoacetyl-2,2-dimethyl-1,3-di-
oxane-4,6-dione (I, R = Me) as model compound and
found that it reacts under mild conditions with ali-
phatic amines and p-methoxyaniline to give enamino
derivatives IVa–IVd in 82–96% yield (Scheme 1). The
By heating of enamines IVa–IVd in boiling toluene
for 30 min we obtained the corresponding pyridine-
carboxylic acids Va–Vd which, according to the
1H NMR data, are completely enolized. The enol form
Scheme 1.
O
O
O
O
O
O
O
O
O
O
R
OH
Me
Me
R
O
R
O
O
I
II
III
R'NH2
MeNH2
H
H
H
O
O
O
O
NR'
Me
O
O
O
OH
N
O
O
H
Me
Me
Me
N
Me
O
R'
R'
IVa–IVd
Va–Vd
VIa–VId
IV–VI, R = Me: R' = Me (a), Pr (b), Bzl (c), C6H4OMe-4 (d).
1070-4280/04/4009-1329 © 2004 MAIK “Nauka/Interperiodica”

RUBINOV et al.
1330
is stabilized by intramolecular hydrogen bonds. Unlike
derivatives of pyran II, compounds Va–Vd do not
undergo decarboxylation on prolonged heating in
boiling toluene. However, pyridinecarboxylic acids
Va–Vd were converted into the corresponding N-sub-
stituted 6-methyl-1,2,3,4-tetrahydropyridine-2,4-di-
ones VIa–VId in 85–90% yield by heating for 3–4 h
in diethylene glycol dimethyl ether at 160°C. 1,6-Di-
methyl-1,2,3,4-tetrahydropyridine-2,4-dione (VIa) was
also synthesized in 20% yield from 6-methylpyrandi-
one III, following the procedure described in [5]. The
products obtained by the two methods had identical
physical constants. We failed to reproduce the yield
given in [5], and our attempts to obtain by the same
procedure compounds VIb–VId (using aqueous
medium, methanol, and acetic acid) were unsuccessful.
General procedure for the synthesis of enamines
IVb–IVd. A mixture of 2.28 g (10 mmol) of 5-aceto-
acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (I) and
10 mmol of the corresponding amine in 20 ml of
chloroform was stirred for 8–10 h at room temperature.
When the reaction was complete (TLC), the mixture
was washed with 10 ml of 1% hydrochloric acid and
water and dried over anhydrous magnesium sulfate,
and the solvent was distilled off under reduced
pressure.
2,2-Dimethyl-5-[(Z)-3-propylamino-2-butenoyl]-
1,3-dioxane-4,6-dione (IVb). Yield 2.60 g (97%),
mp 130–131°C (decomp.). IR spectrum, ν, cm–1: 3285,
1
3100, 1690, 1630, 1580, 1535. H NMR spectrum, δ,
ppm: 1.04 t (3H, CH3CH2, J = 7.5 Hz), 1.68 m (2H,
CH3CH2), 1.74 s (6H, CH3CCH3), 2.18 s (3H, CH3),
3.38 m (2H, NCH2), 6.40 s (1H, CH=C), 8.92 br.s (1H,
NH), 15.90 s (1H, OH, enol). Found, %: C 58.10;
H 7.22; N 5.43. [M]+ 269. C13H19NO5. Calculated, %:
C 57.98; H 7.11; N 5.20.
EXPERIMENTAL
The IR spectra were recorded in KBr on a UR-20
1
spectrometer. The H NMR spectra were obtained on
a Bruker AT-200 instrument using DMSO-d6–chloro-
form-d (1:2) (compounds VIb–VId) and chloroform-d
as solvents (the other products); the chemical shifts
were measured relative to tetramethylsilane as internal
reference. The mass spectra were recorded on
an MKh-1320 mass spectrometer. The melting points
were determined on a Boetius device. The progress of
reactions and the purity of products were monitored by
TLC on Silufol UV-254 or Alufol UV-254 plates; spots
were visualized under UV irradiation, followed by
spraying with a solution of iron(III) chloride.
5-[(Z)-3-(Benzylamino)-2-butenoyl]-2,2-di-
methyl-1,3-dioxane-4,6-dione (IVc). Yield 2.90 g
(96%), mp 136–137°C (decomp.). IR spectrum, ν,
1
cm–1: 3285, 3100, 1690, 1630, 1580, 1535. H NMR
spectrum, δ, ppm: 1.68 s (6H, CH3CCH3), 2.18 s (3H,
CH3), 4.56 d (2H, CH2Ph, J = 6.0 Hz), 6.48 s (1H,
CH=C), 7.20–7.40 m (5H, C6H5), 9.16 br.s (1H, NH),
16.00 s (1H, OH, enol). Found, %: C 58.10; H 7.22;
N 5.43. [M]+ 303. C16H17NO5. Calculated, %: C 63.36;
H 5.65; N 4.62.
5-[(Z)-3-(4-Methoxyphenylamino)-2-butenoyl]-
2,2-dimethyl-1,3-dioxane-4,6-dione (IVd). Yield
3.20 g (96%), mp 135-138°C (decomp.). IR spectrum,
ν, cm–1: 3295, 1705, 1650, 1620, 1585, 1520. 1H NMR
spectrum, δ, ppm: 1.74 s (6H, CH3CCH3), 2.12 s (3H,
CH3), 3.84 s (3H, OCH3), 6.60 d (1H, CH=C, J =
1.5 Hz), 6.94 d (2H, C6H4, J = 9.0 Hz), 7.10 d (2H,
C6H4, J = 9.0 Hz), 10.20 br.s (1H, NH), 16.10 d
(1H, OH, enol, J = 1.5 Hz). Found, %: C 61.17;
H 5.68; N 4.37. [M]+ 333. C17H19NO6. Calculated, %:
C 61.25; H 5.75; N 4.20.
2,2-Dimethyl-5-[(Z)-3-methylamino-2-butenoyl]-
1,3-dioxane-4,6-dione (IVa). To a solution of 2.28 g
(10 mmol) of 5-acetoacetyl-2,2-dimethyl-1,3-dioxane-
4,6-dione (I) in 20 ml of methanol we added 2 ml of
25% aqueous methylamine, and the mixture was
stirred for 10 h at room temperature. Methanol and
excess methylamine were removed under reduced
pressure, the product was extracted into chloroform,
and the extract was washed with 1% hydrochloric acid
and water, dried over anhydrous magnesium sulfate,
and evaporated on a rotary evaporator. Yield 1.98 g
(82%), mp 145–147°C (decomp.). IR spectrum, ν,
cm–1: 3260, 3150, 1695, 1680, 1630, 1550, 1500.
1H NMR spectrum, δ, ppm: 1.71 s (6H, CH3CCH3),
2.17 s (3H, CH3), 3.10 d (3H, NCH3, J = 5.5 Hz),
6.42 s (1H, CH=C), 8.85 br.s (1H, NH), 15.91 s (1H,
OH, enol). Found, %: C 54.60; H 6.31; N 6.01.
[M]+ 241. C11H15NO5. Calculated, %: C 54.77; H 6.27;
N 5.81.
General procedure for the synthesis of pyridine-
carboxylic acids Va–Vd. A solution of 5 mmol of
enamine IVa–IVd in 20 ml of toluene was heated for
0.5 h under reflux. The mixture was cooled to room
temperature and was placed for several hours in
a freezing chamber. The crystals were filtered off,
washed with cold toluene on a filter, and dried under
reduced pressure.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 9 2004

SYNTHESIS OF 1,6-DISUBSTITUTED 2,4-PYRIDINEDIONES
1331
1,6-Dimethyl-1,2,3,4-tetrahydropyridine-2,4-di-
one (VIa). Yield 0.60 g (86%), mp 235–236°C; pub-
lished data [5]: mp 230°C. IR spectrum, ν, cm–1: 1665,
1,6-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyri-
dine-3-carboxylic acid (Va). Yield 0.78 g (85%),
mp 185–187°C (decomp.). IR spectrum, ν, cm–1: 1705,
1
1
1630, 1680, 1550, 1500. H NMR spectrum, δ, ppm:
1620, 1605, 1560, 1500, 1480. H NMR spectrum, δ,
2.30 s (3H, CH3), 3.85 s (3H, CH3), 6.05 br.s (2H,
CH=C), 10.08 br.s (1H, OH, enol). Found, %: C 60.60;
H 6.61; N 9.97. [M]+ 139. C7H9NO2. Calculated, %:
C 60.42; H 6.52; N 10.07.
ppm: 2.41 s (3H, CH3), 3.90 s (3H, NCH3), 6.11 s (1H,
CH=C), 13.31 s (1H, OH), 15.45 br.s (1H, OH, enol).
Found, %: C 52.60; H 5.05; N 7.61. [M]+ 183.
C8H9NO4. Calculated, %: C 52.46; H 4.95; N 7.65.
6-Methyl-1-propyl-1,2,3,4-tetrahydropyridine-
2,4-dione (VIb). Yield 0.70 g (84%), mp 199–200°C.
IR spectrum, ν, cm–1: 1665, 1630 s, 1580, 1550, 1500.
1H NMR spectrum, δ, ppm: 0.98 t (3H, CH3CH2, J =
7.5 Hz), 1.66 m (2H, CH3CH2), 2.32 s (3H, CH3), 3.92
(2H, NCH2), 5.90 d (1H, CH=C, J = 2.5 Hz), 5.98 d
(1H, CH=C, J = 2.5 Hz), 10.50 br.s (1H, OH, enol).
Found, %: C 64.72; H 7.81; N 8.14. [M]+ 167.
C9H13NO2. Calculated, %: C 64.65; H 7.84; N 8.38.
6-Methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydro-
pyridine-3-carboxylic acid (Vb). Yield 0.93 g (88%),
mp 96–97°C (decomp.). IR spectrum, ν, cm–1: 1705,
1
1620, 1605, 1560, 1500, 1480. H NMR spectrum, δ,
ppm: 1.02 t (3H, CH3CH2, J = 7.5 Hz), 1.68 m
(2H, CH3CH2), 2.44 s (3H, CH3), 3.96 m (3H, NCH2),
6.08 s (1H, CH=C), 13.26 s (1H, OH), 15.40 br.s
(1H, OH, enol). Found, %: C 55.57; H 7.15; N 6.60.
[M]+ 211. C10H13NO4. Calculated, %: C 56.87; H 6.20;
N 6.63.
1-Benzyl-6-methyl-1,2,3,4-tetrahydropyridine-
2,4-dione (VIc). Yield 1.00 g (93%), mp 208–210°C.
IR spectrum, ν, cm–1: 1665, 1630 s, 1580, 1550, 1500.
1H NMR spectrum (CDCl3–DMSO-d6), δ, ppm: 2.20 s
(3H, CH3), 5.24 s (2H, CH2Ph), 5.80 br.s (2H, CH=C),
7.10–7.34 m (5H, C6H5), 10.10 br.s (1H, OH, enol).
Found, %: C 72.66; H 6.18; N 6.67. [M]+ 215.
C13H13NO2. Calculated, %: C 72.54; H 6.09; N 6.51.
1-Benzyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
pyridine-3-carboxylic acid (Vc). Yield 1.17 g (90%),
mp 142–143°C (decomp.). IR spectrum, ν, cm–1: 1705,
1
1620, 1605, 1560, 1500, 1480. H NMR spectrum, δ,
ppm: 2.38 s (3H, CH3), 5.30 s (2H, CH2Ph), 6.12 s
(1H, CH=C), 7.06–7.40 m (5H, C6H5), 13.42 s (1H,
OH), 15.18 br.s (1H, OH, enol). Found, %: C 65.07;
H 5.13; N 5.36. [M]+ 259. C14H13NO4. Calculated, %:
C 64.86; H 5.05; N 5.40.
1-(4-Methoxyphenyl)-6-methyl-1,2,3,4-tetra-
hydropyridine-2,4-dione (VId). Yield 1.00 g (87%),
mp 278–280°C. IR spectrum, ν, cm–1: 1665, 1630,
1-(4-Methoxyphenyl)-6-methyl-2,4-dioxo-1,2,3,4-
tetrahydropyridine-3-carboxylic acid (Vd). Yield
1.22 g (89%), mp 170–173°C (decomp.). IR spectrum,
ν, cm–1: 1715, 1640, 1620, 1600, 1525, 1500. 1H NMR
spectrum, δ, ppm: 2.04 s (3H, CH3), 3.86 s (3H,
OCH3), 6.12 s (1H, CH=C), 7.08 m (4H, C6H4), 13.50 s
(1H, OH), 14.84 s (1H, OH, enol). Found, %: C 61.18;
H 4.63; N 5.22. [M]+ 275. C14H13NO5. Calculated, %:
C 61.09; H 4.76; N 5.09.
1
1540, 1520. H NMR spectrum (CDCl3–DMSO-d6), δ,
ppm: 1.88 s (3H, CH3), 3.84 s (3H, OCH3), 5.60 d (1H,
CH=C, J = 3.0 Hz), 5.86 d (1H, CH=C, J = 3.0 Hz),
7.04 m (4H, C6H4), 10.30 br.s (1H, OH, enol). Found,
%: C 67.45; H 5.81; N 6.17. [M]+ 231. C13H13NO3.
Calculated, %: C 67.52; H 5.67; N 6.06.
REFERENCES
Decarboxylation of pyridinecarboxylic acids Va–
Vd. A solution of 5 mmol of pyridinecarboxylic acid
IVa–IVd in 20 ml of diethylene glycol dimethyl ether
was heated for 3–4 h at 160°C. When the reaction was
complete (TLC), the mixture was cooled to room tem-
perature and was placed for several hours in a freezing
chamber. The crystals were filtered off, washed on
a filter with cold diethyl ether, and dried under reduced
pressure.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 9 2004