Syntheses of 5-(alkylaminocarbonyl)-4,6-dimethyl-2-pyridones from N- alkyl-3-oxobutanamides

Article abstract of DOI:10.1055/s-1998-2211

1-Alkyl-5-(alkylaminocarbonyl)-4,6-dimethyl-2-pyridones were obtained in high yields from the self-condensation of N-alkyl-3-oxobutanamides in the presence of p-toluenesulfonic acid as a catalyst at 100-110°C for 11-24 hours without solvent.

Full text of DOI:10.1055/s-1998-2211

SYNTHESIS
December 1998
1715
Syntheses of 5-(Alkylaminocarbonyl)-4,6-dimethyl-2-pyridones from N-Alkyl-3-
oxobutanamides
Isao Furukawa,* Hironori Fujisawa, Mitsuru Kawazome, Yasuto Nakai, Tetsuo Ohta
Department of Molecular Science and Technology, Faculty of Engineering, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan
Fax +81(774)656794; E-mail: ifurukaw@mail.doshisha.ac.jp
Received 26 March 1998; revised 7 May 1998
Abstract: 1-Alkyl-5-(alkylaminocarbonyl)-4,6-dimethyl-2-pyri-
dones were obtained in high yields from the self-condensation of
N-alkyl-3-oxobutanamides in the presence of p-toluenesulfonic
acid as a catalyst at 100–110°C for 11–24 hours without solvent.
Table 1. Synthesis of 1-Alkyl-5-(alkylaminocarbonyl)-4,6-dimethyl-
2-pyridones 2a
Product
Time
(h)
Yieldb
(%)
mp
Key words: self-condensation, 5-(alkylaminocarbonyl)-4,6-di-
methyl-2-pyridone, N-alkyl-3-oxobutanamide
2
R
(°C)
2a
2b
2c
2d
Me
Pr
i-Pr
PhCH2
12
11
24
20
97
84
80
92
177.5–178.0
132.5–133.0
128.4–129.1
81.2–82.4
2-Pyridone derivatives are found in the pyridine nucle-
otide cycle in plants and also show several physiological
activities, such as antifungal and antibiotic.1 They have
been prepared by numerous methods,1 for example by the
oxidation of an N-substituted pyridinium salt, by Knove-
nagel-type reaction, such as cross-condensation of
cyanoacetoamide and β-dicarbonyl compounds by basic
catalysts, or by the reaction of 2-pyrones with primary
amines.1–4
a
Satisfactory microanalyses obtained C±0.26, H±0.18, N±0.13; for
2d this was calculated for the monohydrate.
Yield of the isolated product.
b
slowly at lower temperature. Using an equimolar amount
of p-toluenesulfonic acid was effective for this reaction,
while using a half equivalent of acid made the reaction
slow, and no reaction occurred without acid. The reaction
without solvent was convenient for the separation of the
product, because product 2 was obtained by direct column
chromatographic purification of the reaction mixture
without concentration. The product 2b was identified by
spectroscopic and elemental analyses. Its structure was
also confirmed by X-ray crystallographic analysis of a
suitable single crystal of 2b (Figure and Experimental
Section). From the X-ray data, bond lengths and angles
are reasonable for 2-pyridone structure, and the aminocar-
bonyl moiety does not resonance with carbon–carbon
double bonds in 2-pyridone by sterical demand.
We have been studying the chemistry of α-acylketene
O,N-acetals because of their easy synthesis5 and unique
reactivity6 and have found that they were converted to
2-pyridone derivatives.7 A mechanistic study of this reac-
tion resulted an efficient synthetic method for 2-pyridone
derivatives from N-substituted acetoacetamides in the
presence of acid. Although this chemistry is considered
basic, there were few reports on the synthesis of 2-pyri-
done derivatives from acetoacetamide derivatives, in
which the yields were not satisfactory to our surprise.8
Moreover, our procedure was quite simple, in which the
desired product was obtained by heating a mixture of
N-substituted acetoacetamide and p-toluenesulfonic acid
without solvent, and then by column chromatographic pu-
rification of the resulting mixture directly. This may be
so-called “the environmentally friendly” procedure. Here
we wish to describe the detail of this easy and new meth-
od.
Figure. ORTEP Diagram for 4,6-dimethyl-1-propyl-5-(propylami-
nocarbonyl)-2-pyridone 2b showing 50% probability thermal ellip-
soids.
Reaction of N-propyl-3-oxobutanamide (1b) was per-
formed by use of an equimolar amount of p-toluene-
sulfonic acid as a catalyst. When the reaction was per-
formed using a solvent, 4,6-dimethyl-1-propyl-5-(pro-
pylaminocarbonyl)-2-pyridone (2b) was obtained in
moderate yield (for example, benzene: 46%, acetonitrile,
45%, dichloromethane: 14%), while 2b was obtained in
84% yield when the reaction was performed without sol-
vent at 100–110°C for 11 hours. The reaction proceeded
Several N-alkyl-3-oxobutanamides (1) were reacted under
these conditions and converted to 1-alkyl-5-(alkylami-
nocarbonyl)-4,6-dimethyl-2-pyridones 2 in high yields.
Representative results are listed in Table 1, and analytical
data for identification of the products are given in Table 2.

SYNTHESIS
Short Papers
Table 2. Spectral Data of 1-Alkyl-5-(alkylaminocarbonyl)-4,6-dimethyl-2-pyridones 2
1716
2
IR ν (cm–1)
1H NMR (CDCl3, 400 MHz) δ, J (Hz)
2a
1525, 1640
2.14 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.99 (d, 3H, J = 4.4, CH3), 3.37 (s, 3H, CH3), 6.09 (s, 1H, –CH=), 7.42
(br, 1H, NH)
2b
2c
2d
1522, 1640
1525, 1640
1520, 1640
0.96 (t, 3H, J = 7.6, CH2CH2CH3), 1.02 (t, 3H, J = 7.4, CH2CH2CH3), 1.61 (sextet, 2H, J = 7.2, CH2CH2CH3),
1.67 (sextet, 2H, J = 7.2, CH2CH2CH3), 2.14 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.39 (q, 2H, J = 6.6,
NHCH2CH2CH3), 3.81 (t, 2H, J = 7.8, NCH2CH2CH3), 6.13 (s, 1H, –CH=), 6.99 (br, 1H, NH)
1.26 [d, 3H, J = 6.8, CH(CH3)(CH3)], 1.55 [d, 3H, J = 6.8, CH(CH3)(CH3)], 2.11 (s, 3H, CH3), 2.34 (s, 3H,
CH3), 4.24 [d of heptet, 1H, J = 8.0 and 6.8, NHCH(CH3)2], 4.43 [br, 1H, NCH(CH3)2], 6.05–6.30 (m, 2H,
–CH= and NH)
2.15 (s, 3H, CH3), 2.22 (s, 3H, CH3), 4.55 (d, 2H, J = 5.6, NHCH2C6H5), 5.17 (s, 2H, NCH2C6H5), 6.27 (s, 1H,
–CH=), 7.07–7.35 (m, 10H, Ar)
N-Isopropyl-3-oxobutanamide (1c) also converted to a
sterically hindered five-substituted dihydropyridine de-
rivative in 80% yield.
the reaction of diketene and primary amines, and the sim-
ple operation affords the product. A variety of synthetic
procedures were reported for 2-pyridone derivatives, but
still most of our products are new compounds. That is to
say, our method becomes complementary to others.
Possible mechanism of this reaction is shown in the
Scheme. Double condensations and double dehydrations
seem to afford the product. Claisen and Meyer reported
the condensation of 3-oxobutanamide giving 5-aminocar-
bonyl-4,6-dimethyl-2-pyridone in low yield when being
heated,8b but Kato et al. reinvestigated this reaction and
proposed a different structure for the products, 3-acetyl-
4-amino-6-methyl-2-pyridone (byproduct, 3%) and 2,6-
dimethyl-4-pyrimidone (main product, 52%).8c, d Even
though pyrolysis of 3-oxobutanamide gave the different
products, Sato reported that the self-condensation of
N-methyl-3-oxobutanamide in benzene in the presence of
sulfuric acid afforded the 1,4,6-trimethyl-5-(methylami-
nocarbonyl)-2-pyridone in 63% yield with only elemental
analysis, IR, and UV data.8a
Self-condensation of N-substituted 3-oxobutanamide was
demonstrated to construct 6-membered heterocyclic com-
pound, 2-pyridone derivatives. Using no solvent afforded
the product in quite high yields by simple treatment of the
reaction mixture.
1H NMR spectra were measured on a JEOL JNM A-400 (400 MHz)
spectrometer using TMS as an internal standard. IR spectra were mea-
sured on a Shimadzu IR-408 spectrophotometer. GC-MS were re-
corded on a Shimadzu GP2000A instrument. Elemental analysis were
performed at the Microanalytical Center of Kyoto University. X-ray
analysis was conducted on a Rigaku RASA-7R four-circle diffrac-
tometer. Mps were measured on a Yanako Model MP and were not
corrected.
All solvents were dried by standard methods.10 Commercially avail-
able compounds were used without purification. N-Alkyl-3-oxobu-
tanamides 1 were prepared by modified methods according to the lit-
erature method.11
N-Alkyl-3-oxobutanamides 1; General Procedure:
In a 25-mL flask was placed a mixture of diketene (50 mmol) and
MeCN (100 mL). To this was added an amine (50 mmol) slowly at
r.t., and the mixture was stirred for 4 h. The resulting mixture was
purified by column chromatography (silica gel 60, EtOAc).
N-Alkyl-5-(alkylaminocarbonyl)-4,6-dimethyl-2-pyridones 2;
General Procedure:
Into a 25-mL test tube were introduced N-alkyl-3-oxobutanamide 1
(2.0 mmol) and anhyd TsOH (0.38 g, 2.0 mmol). The mixture was
heated at 100–110°C for 11–24 h. The resulting mixture was purified
by column chromatography (silica gel 60, hexane/EtOAc=1, and
EtOAc/acetone=1).
Scheme
Self-condensation of β-oxo carbonyl compounds have
been reported in only two cases. One is above and another
is the condensation of ethyl 3-oxobutanoate in the pres-
ence of sulfuric acid to give 5-carbonyl-4,6-dimethyl-2-
pyrone in only 27% yield.9
Crystallographic Data Collections and Structure Determination
of 2b:12
The crystals of 2b suitable for X-ray diffraction studies were prepared
by recrystallization from hexane/Et2O. Relevant crystal and data sta-
tistics are summarized in Table 3. The unit cell parameter at 20°C was
determined by a least-squares fit to 2θ values of 25 strong higher re-
flections. Three standard reflections were chosen and monitored ev-
ery 150 reflections and showed no significant intensity decay during
This synthetic way gives a facile method for the prep-
aration of 1-alkyl-5-(alkylaminocarbonyl)-4,6-dimethyl-
2-pyridone derivatives. That is, the starting materials,
N-substituted 3-oxobutanamides, are easily prepared by

SYNTHESIS
December 1998
1717
Table 3. Crystallographic Data for 4,6-Dimethyl-1-propyl-5-(propylaminocarbonyl)-2-pyridone (2b)
Crystal Parameters and Measurement of Intensity Data
Chemical Formula
Crystal
Crystal System
a (Å)
C14H22N2O2
colorless, prismatic
monoclinic
13.204(3)
13.616(3)
1483.3(6)
1.121
Rigaku AFC7R
Mo, 0.71069 (graphite monochromated)
ω-2θ
1.68+0.30 tanθ
3644
0.063
Formula Weight
Size (mm)
Space Group
b (Å)
β (deg)
Z
250.34
0.4×0.1×0.4
P21/c
8.647(3)
107.41(2)
4
c (Å)
V (Å3)
Dcalc (g/cm3)
Diffractometer
Radiation (Å)
Scan Type
µ (MoKα) (cm–1)
0.75
Scan Rate (°/min)
2θ max (deg)
No of obsd.
RW
16
55.0
1676 (I>3σ(I))
0.052
Scan Width (deg)
No of Unique Data
R
Goodness of Fit
4.53
Max Shift/Error
0.16
(1) Bailey, T. D.; Goe, G. L.; Scriven, E. F. V. In Heterocyclic
Compounds; Newkome, G. R., Ed.; Wiley: New York, 1984;
Vol. 14, Part 5, p 1.
(2) Smith, D. M. In Comprehensive Organic Chemistry; Sammes,
P. G., Ed.; Pergamon: Oxford, 1979; Vol. 4, p 3.
McKillop, A.; Boulton, A. J. In Comprehensive Heterocyclic
Chemistry; Boulton, A. J., Mckillop, A., Eds.; Pergamon: Ox-
ford, 1984; Vol. 2, p 67.
(3) Oxidation of N-substituted pyridinium salts, see:
Prill, E. A.; McElvain, S. M. Org. Synth., Coll. Vol. II 1943,
419.
Sugasawa, S.; Sakurai, K.; Okayama, T. Proc. Imp, Acad.
(Tokyo) 1940, 16, 225; Chem. Abstr. 1940, 34, 6940.
(4) Knovenagel-type reaction, see: ref 1 and Jones, G. Org. React.
1967, 15, 204. The reaction of 2-pyrone, see: ref 1.
(5) Moussounga, J.; Bouquant, J.; Chuche, J. Synthesis 1994, 483.
Furukawa, I.; Fujisawa, H.; Abe, T.; Ohta, T. submitted for
publication.
Table 4. Selected Bond Distances and Angles for 4,6-Dimethyl-1-
propyl-5-(propylaminocarbonyl)-2-pyridone (2b)
Intramolecular Distances (Å) (standard deviation)
O(1)–C(1) 1.243(4) O(2)–C(7) 1.219(4) N(1)–C(1) 1.404(4)
N(1)–C(5) 1.385(4) N(1)–C(9) 1.479(4) N(2)–C(7) 1.322(4)
C(1)–C(2) 1.434(5) C(2)–C(3) 1.357(5) C(3)–C(4) 1.417(4)
C(3)–C(6) 1.516(5) C(4)–C(5) 1.364(4) C(4)–C(7) 1.513(4)
C(5)–C(8) 1.498(5)
Selected Bond Angles (deg) (standard deviation)
C(1)–N(1)–C(5)
C(5)–N(1)–C(9)
O(1)–C(1)–C(2)
C(1)–C(2)–C(3)
C(2)–C(3)–C(6)
C(3)–C(4)–C(5)
C(5)–C(4)–C(7)
N(1)–C(5)–C(8)
122.8(3)
121.6(3)
124.4(4)
122.6(4)
119.7(4)
120.7(3)
120.6(3)
117.7(3)
C(1)–N(1)–C(9)
O(1)–C(1)–N(1) 120.2(3)
115.6(3)
N(1)–C(1)–C(2)
C(2)–C(3)–C(4)
C(4)–C(3)–C(6)
C(3)–C(4)–C(7)
N(1)–C(5)–C(4)
C(4)–C(5)–C(8)
115.4(3)
119.1(3)
121.2(4)
118.6(3)
119.4(3)
122.8(3)
(6) Furukawa, I.; Abe, T.; Fujisawa, H.; Ohta, T. Tetrahedron
1997, 53, 17643.
(7) Furukawa, I.; Fujisawa, H.; Kawazome, M.; Nakai, Y.; Ohta, T.
submitted for publication.
(8) (a) Sato, M. Dissertation, Tohoku University School of Medi-
cine, 1972.
the data collection (less than 3%). The crystal structure was solved by
the direct method (Sir) and refined by the full-matrix least squares
method. Measured nonequivalent reflections with I>3.0σ(I) were
used for the structure determination. In the subsequent refinement the
function Σω(|Fo|-|Fc|)2 was minimized, where |Fo| and |Fc| are the ob-
served and calculated structure factors amplitudes, respectively. The
(b) Claisen, L.; Meyer, K. Chem. Ber. 1902, 35, 583.
(c) Kato, T.; Yamanaka, H.; Shibata, T. Chem. Pharm. Bull.
1967, 15, 921.
(d) Kato, T.; Yamanak, H.; Kawamata, J.; Shibata, T. Chem.
Pharm. Bull. 1968, 16, 1835.
agreement indices are defined as R = Σ||Fo|–|Fc||/Σ|Fo| and Rw
=
[Σω(|Fo|–|Fc|)2/Σω(|Fo|)2]1/2 where ω-1 = σ2(Fo) = σ2(Fo )/(4Fo ). The
positions of all non-hydrogen atoms and aromatic hydrogen were
found from a difference Fourier electron density map and the posi-
tions of other hydrogen atoms were determined by calculations, and
then refined anisotropically for non-hydrogen atoms and isotropically
for hydrogen atoms. All calculations were performed using the TEX-
SAN crystallographic software package. Selected bond distances and
angles are summarized in Table 4.
2
2
(9) Schreiber, R. S.; Fall, H. H. Org. Synth. 1952, 32, 76.
(10) Perrin, D. D.; Armarego, W. L. F. In Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
(11) Bormann, D. In Houben-Weyl, 4th ed., Vol. VII/4; Thieme:
Stuttgart, 1968; p 233.
(12) Crystallographic data was deposited at the Cambridge Crystal-
lographic Data Centre.
We thank Dr. Takayuki Yamashita for helpful discussions during the
course of this work. This work was partially supported by a grant to
RCAST at Doshisha University from the Ministry of Education,
Japan.