An efficient synthesis of N1-substituted 2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide via enolate salts

Article abstract of DOI:10.1016/j.tet.2008.02.095

Various 2-(2-cyano-2-carbamoyl-1-ethenyl)-5,5-dimethyl-3-oxo-1-cyclohexen-1-olates substituted in the amide group with dialkylammonium or sodium cations were prepared via reactions of N-substituted cyanoacetamides with dimedone-DMFDMA adduct by a one-pot,

Full text of DOI:10.1016/j.tet.2008.02.095

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4649e4655
www.elsevier.com/locate/tet
An efficient synthesis of N1-substituted 2,5-dioxo-1,2,5,6,7,8-
hexahydro-3-quinolinecarboxamide via enolate salts
*
Sergey A. Yermolayev, Nikolay Yu. Gorobets , Elena V. Lukinova, Oleg V. Shishkin,
Svetlana V. Shishkina, Sergey M. Desenko
State Scientific Institution ‘Institute for Single Crystals’ of National Academy of Science of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine
Received 23 October 2007; received in revised form 13 February 2008; accepted 28 February 2008
Available online 4 March 2008
Abstract
Various 2-(2-cyano-2-carbamoyl-1-ethenyl)-5,5-dimethyl-3-oxo-1-cyclohexen-1-olates substituted in the amide group with dialkylammo-
nium or sodium cations were prepared via reactions of N-substituted cyanoacetamides with dimedoneeDMFDMA adduct by a one-pot, two-step
protocol. The salts obtained were used in reactions with N-nucleophiles for further synthesis of the N1-substituted 2,5-dioxo-1,2,5,6,7,8-hexa-
hydro-3-quinolinecarboxamides that are analogues of well-known pharmaceuticals. The structure of the salts and the N1-substituted 2,5-dioxo-
1,2,5,6,7,8-hexahydro-3-quinolinecarboxamides was established by means of spectroscopic and X-ray diffraction studies.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 2-Pyridones; Dimedone; Enolates; Primary amines
1. Introduction
reported to be inotropic agents,5,6 specific non-nucleoside
reverse transcriptase inhibitors of human immunodeficiency
virus-1 (HIV-1),7,8 and other valuable biologically active
agents.9,10 Therefore, the synthesis of novel compounds on the
basis of a 2-pyridone scaffold attracts considerable attention.11
One of the approaches to a range of 2-pyridone derivatives
6 uses the reactivity of methylene active nitriles 4 in their
reactions with dicarbonyl compoundeDMFDMA adducts 512
(Scheme 1). In this reaction, however, in several cases, un-
cyclised salts that include 4-cyano-1,3-butadienolate moiety,
Compounds that contain the 2-pyridone ring exhibit different
biological activities. For instance, pirfenidone 1 is an inhibitor
of cytokines, which can cause death during serious inflamma-
tion1 (Chart 1). Huperzine A 2 is a natural alkaloid that possesses
cholinesterase inhibitor properties. This drug has been used
worldwide for decades as a short-term memory enhancer and
also in Alzheimer’s disease treatment.2,3 Ciclopirox 3 possesses
antifungal activity.4 Some 2-pyridone derivatives are also
H3C
CH3
R3
Me
R1
R2
R1
R2
R1
R2
R3
O
N
4
N
NH2
DMFDMA
neat
Me
N
O
H
i-PrOH, pipyridine,
MW, 100 °C, 5 min
O
H
O
N
H
N
OH
O
N
H
O
5
6
O
1
2
3
Ar
O
R5
O
N
R5
O
R5
R1
R1
Pirfenidone
Huperzine A
Ciclopirox
N
R1
CN
R2
N
Ar
R2
O-
+NH3Ar
DMF, KOH
Chart 1.
R2
O
7
8
9
* Corresponding author. Fax: þ38 572 3409343.
E-mail address: gorobets@isc.kharkov.com (N.Yu. Gorobets).
Scheme 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.095

4650
S.A. Yermolayev et al. / Tetrahedron 64 (2008) 4649e4655
Table 1
The isolated yields for the enolates 14aej
e.g., 8 (Scheme 1) were obtained as byproducts or intermedi-
ates. Analogous salts were also isolated in a number of other
works.13e23 In spite of the obvious synthetical potential of these
salts, they were utilized mostly for intramolecular cyclization
into the pyridones 6 or, after their hydrolysis, into 2-pyranone
derivatives,14,15,19 whereas such cyclization with participation
of N-nucleophiles could lead to more diverse range of 1N-
substituted 2-pyridones 9. Thus, Ziegler and Wolfbeis postu-
lated the formation of enolates 8 in the course of the synthesis
of 1N-substituted 2-pyridones 9 starting from enamines 7
(Scheme 1). This reaction was carried out applying malonodi-
nitrile and ethyl cyanoacetate as methylene active nitriles in a
strong base medium.18 Unfortunately, an application of more
diverse building blocks such as substituted cyanoacetamides
in this reaction is unlikely to be successful because, under the
strong base conditions, the intramolecular cyclization may
involve the amide group.24,25
In continuation of the work,12 we aimed to develop a facile
and efficient method for preparation of various salts 8 in the
current study, and to apply these enolates as starting materials
for synthesis of the N1-substituted 2,5-dioxo-1,2,5,6,7,8-hexa-
hydro-3-quinolinecarboxamide derivatives. Whereas in the
previous work,12 attention was focused on diversity of the di-
carbonyl compounds and methylene active nitriles; in the
current study the 2-pyridone derivatives are diversified by var-
ious N-substituted cyanacetanilides26,12 and aromatic/hetero-
aromatic amines applying dimedone as a representative
dicarbonyl compound.
R
Catþ
Yield (%)
14aa
14bb
14cb
14da
14ec
14fc
14ga
14hc
14ic
14jc
a
H
Naþ
62
90
67
29
52
62
20
50
56
77
H
Me
Me2NHþ2
Me2NHþ2
Naþ
Me
Me
(CH2)5NHþ2
(CH2)5NHþ2
Naþ
(CH2)5NHþ2
(CH2)5NHþ2
(CH2)5NHþ2
CH2C6H5
CH2C6H5
3-MeeC6H4
2-MeOeC6H4
2-Thiazolyl
Reaction conditions: EtOH, Na (1 equiv).
i-PrOH, piperidine (0.03 equiv).
i-PrOH, piperidine (2 equiv).
b
c
are formed. Generally, by varying the nature of the prevalent
base in the reaction mixture, it is possible to obtain the enolates
14aej with different cations (sodium, dimethylammonium,
piperidinium cations). However, in the case of the cyanoacet-
amide 13 (R¼H) the dimethylammonium enolate 14b (R¼H)
was formed in fair amounts in the course of our attempts to
synthesize a corresponding piperidinium salt, in spite of consid-
erable prevalence of piperidine in the reaction mixture. Also, in
the case of aromatic substituent R in the amide group, the appli-
cation of sodium ethylate as a basic medium did not lead to
isolation of the desired sodium salts.
It should be pointed, that this one-pot reaction applies
the same starting materials (10, 11, 13) that under microwave
irradiation gave 2-pyridone derivatives,12 however, isolation of
the intermediate salts from this reaction allows them to be
applied further in the synthesis of N1-substituted 2-pyridone
derivatives.
2. Results and discussion
The preparation of the desired salts 14 was carried out
in one-pot by the reaction of dimedone 10, dimethylforma-
mide dimethylacetal (DMFDMA) 11, and N-substituted cyan-
acetamides 13 in the presence of a base at room temperature
(Scheme 2). It is necessary to perform this synthesis starting
from the reaction of dimedone 10 with DMFDMA 11, for it
was shown12 that the product of reaction between DMFDMA
11 and methylene active nitrile 13 did not react with dimedone
10. At room temperature, the salt formation proceeded fast
enough without formation of the undesired cyclization product
6. The enolates 14 were isolated as pale yellow precipitates by
simple filtration from the reaction mixture in moderate to good
yields (Table 1) and used in further transformations without ad-
ditional purification. The salts are stable in the solid state at
least during shelf-storage for a month, however, in DMSO-d6
solution they slowly decompose. When piperidine is used as
a base in catalytic amounts, dimethylammonium salts 14b,c
The salts 14 obtained easily reacted with N-nucleophiles
such as aromatic and heteroaromatic primary amines including
ortho-phenylenediamine 15 in acetic acid at room temperature
leading to N-substituted 2-pyridones 16 (Scheme 3, Table 2).
The reaction yields of the 2-pyridones 16aej did not depend
on the nature of the salt cation. However, the overall yields
of these two consecutive stages were higher using the enolates
with the dialkylammonium cations because of higher yields of
the corresponding salts.
O
R1
O
O
O
O
R1
N
H
R2
NH2
N
H
HOAc
rt
CN
+
Me
Me
Me
Me
O-
N
Cat+
R2
16a-j
14
15
Scheme 3.
O
O
O
O
O
R
R
N
H
N
H
Me
Me
Me
13
N
N
CN
neat
+
CN
Me
Me
Me
Me
Me
Me
Me
Me
Me
rt, 5 min
EtOH or i-PrOH
base, rt
O
O-
O
O
O
Cat+
10
11
12
14a-j
Scheme 2.

S.A. Yermolayev et al. / Tetrahedron 64 (2008) 4649e4655
4651
Table 2
The yields for quinolinecarboxamide derivatives 16aej
O
O
N
H
Ph
R1
R2
Yields (%)
CN
O-
14ha
16a
16b
16c
16d
16e
16f
16g
16h
16i
H
4-NEt2eC6H4
2-NO2eC6H4
2-MeeC6H4
Ph
73
60
78
82
74
74
89
77
66
75
H
O-
O
O
H
2-Thiazolyl
H
N
H
Ph
CN
14hb
O
O
2-MeOeC6H4
CH2C6H5
Me
4-MeeC6H4
4-MeOeC6H4
4-MeOeC6H4
2-NH2eC6H4
3-Py
O-
N
H
H
2-Thiazolyl
CN
14hc
16j
Chart 2.
3. Structural elucidation
The 14hb resonance structure (Chart 2) makes the main con-
tribution into the structure of the anion and the negative charge
is localized mainly on the O(2) atom, which is connected with
piperidine by intermolecular hydrogen bond N(3)eH(3Nb)/
All signals in 1H, 13C NMR spectra correspond to the
presumed structure of the obtained salts 14aej. In IR spectra,
characteristic signals of the nitrile and carbonyl groups were
observed. Employing mass spectrometry with EI ionization
did not allow any specific signals of the salts to be observed be-
cause of their instability in such conditions. Therefore, the mass
spectrometry with FAB ionization was applied successfully. In
such mass spectra, peaks corresponding to the cation and the
anion were observed. For the complete structural elucidation,
an X-ray diffraction study of the compound 14h was performed,
which confirmed the presumed salt structure (Fig. 1). From the
crystallographic data it can be assumed that the positive charge
is localized on the protonated N(3) atom of the piperidine. All
hydrogen atoms were located from difference maps of the elec-
tron density and the N(3)eC(20) and N(3)eC(24) bonds are
0
ꢁ
˚
O(2) (1ꢀx, 1ꢀy, 1ꢀz) H/O 1.79 A NeH/O 166 . The
˚
O(2)eC(5) bꢀond (1.272(2) A) is very similar to the mean value
˚
for the CeO bond (1.280 A).
In the course of reaction between the enolates 14 and N-
nucleophiles 15, the formation of alternative products, 2,5-di-
oxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide 16 and
imine 16* is possible (Chart 3). Determination of the reaction
1
product structure was performed by means of H, 13C NMR
spectroscopy, and X-ray diffraction study (Fig. 2). The tetrahy-
drocycle of the compound 16e has an asymmetric half-chair
conformation. Deviation of the C(3) and C(4) atoms from
˚
the mean plane of remaining atoms of the cycle are 0.46 A
˚
˚
˚
and ꢀ0.28 A, respectively. The carbamide substituent lies in
longer (1.498(3) A and 1.515(3) A, respectively) than mean
value27 for NeCsp bond in the neutral molecule (1.473 A).
3
˚
O
O
O
O
O
The analysis of the bond lengths in the anion demonstrates
that the C(1)eC(6) and C(5)eC(6) bonds have the equal value
˚
1.465(2) A, the O(1)eC(1), O(2)eC(5), and O(3)eC(9) bonds
R1
R1
N
H
N
H
Me
Me
Me
Me
9
O
N
N
R2
R2
˚
are longer (1.248(2) A, 1.272(2) A, and 1.261(2) A,
˚
˚
16
16*
˚
respectively) in comparison with their mean value 1.210 A,
˚
the C(6)eC(7) bond is shortened (1.433(2) A) (the mean value
Chart 3.
˚
is 1.455 A) and the C(7)eC(8) bond is 1.393(2) A (the mean
˚
˚
value is 1.316 A). Such redistribution of the electron density
allows to assume that the structure of this molecule is the super-
position of three resonance structures (Chart 2).
Figure 1. The molecular structure of salt 14h. The atom numbering corre-
sponds to that in X-ray analysis data.
Figure 2. The molecular structure of salt 16e. The atom numbering corre-
sponds to that in X-ray analysis data.

4652
S.A. Yermolayev et al. / Tetrahedron 64 (2008) 4649e4655
the plane of pyridine ring (the C(7)eC(8)eC(10)eO(2) tor-
sion angle is 0.1(2)ꢁ), probably, as a result of the formation
of the intramolecular hydrogen bond N(2)eH(2Nb)/
O(3)H/O 2.04 A NeH/O 133 . The phenyl substituent is
almost orthogonal with respect to the pyridine ring (the
C(9)eN(1)eC(11)eC(12) torsion angle is 100.7(1)ꢁ).
In 13C NMR spectra, the reaction product has a key signal
at d 160.3 ppm that was assigned to the carbon at position 9
(Chart 3).
5.2.1. Dimethylammonium 2-(2-carbamoyl-2-cyano-1-
ethenyl)-5,5-dimethyl-3-oxo-1-cyclohexen-1-olate (14b)
Yield 9.04 g, 90%. Spectral data for the product was same
as described in Ref 12; FABMS m/z: 235 (Anþ2Hþ), 280
(AnþCatþHþ).
ꢁ
˚
5.2.2. Dimethylammonium 2-(2-cyano-2-methylcarbamoyl-
1-ethenyl)-5,5-dimethyl-3-oxo-1-cyclohexen-1-olate (14c)
Yield 6.54 g, 62%; mp 111e113 ꢁC (dec); dH (200 Hz,
DMSO-d6) 0.91 (6H, s, Me), 2.07 (4H, s, CH2), 2.53 (6H, s,
NMe2), 2.63 (3H, d, J 4.6 Hz, NMe), 6.97 (1H, q, J 4.6 Hz,
NH), 8.03 (1H, s, CH), 8.18 (2H, br s, NH2); dC (50 MHz,
DMSO-d6) 27.1, 29.0, 30.1, 35.2, 52.2, 88.5, 110.1, 120.1,
145.1, 167, 192.6; nmax (KBr) 1246, 1395, 1486, 1531, 1647,
2186, 2763, 2948, 3172, 3381; FABMS m/z: 249 (Anþ2Hþ),
294 (AnþCatþHþ). Purification caused decomposition of
the salt that is why the CHN analysis was not representative.
4. Conclusion
In summary, a new synthetic method for N1-substituted 2-
pyridone derivatives has been developed. Starting resonance-
stabilized enolates 14aej were obtained by a one-pot reaction
of dimedone, DMFDMA ,and different N-substituted cyano-
acetamides. The isolated yields (20e90%) depend on the cation
nature and substituted cyanoacetamide structure. The reaction
of the salts obtained 14aej with different N-nucleophiles
affords diverse N-substituted 2,5-dioxo-1,2,5,6,7,8-hexahy-
dro-3-quinolinecarboxamides 16aej. The application of di-
alkylammonium salts was found to be more productive than
sodium salts.
5.3. General procedure for the preparation of the
hexahydropyridinium 2-(2-carbamoyl-2-cyano-1-ethenyl)-
5,5-dimethyl-3-oxo-1-cyclohexen-1-olates (14e, f, hej)
The enamine 12, obtained as described above from dime-
done 10 (5.00 g, 0.036 mol) and DMFDMA (4.28 g,
0.036 mol), was dissolved in 2-propanol (30 mL). Then piperi-
dine (6.19 g, 0.072 mol), corresponding cyanacetamide 13
(0.036 mol) were added consecutively to the solution and
stirred at room temperature for 1 h. A pale yellow precipitate
of the salt was formed, removed by filtration, washed with ether,
and dried.
5. Experimental
5.1. General
Starting materials were obtained from commercial suppliers
and used without further purification. Melting points (ꢁC) were
measured using Koeffler melting point apparatus. 1H NMR and
13C NMR spectra were recorded at 200 MHz (50 MHz for 13
C
5.3.1. Hexahydropyridinium 2-(-2-cyano-2-methylcarbamoyl-
1-ethenyl)-5,5-dimethyl-3-oxo-1-cyclohexen-1-olate (14e)
Yield 6.23 g, 52%; mp 121e123 ꢁC (dec); dH (200 MHz,
DMSO-d6) 0.91 (6H, s, Me), 1.51e1.73 (6H, m, (CH2)3),
2.08 (4H, s, CH2), 2.64 (3H, d, J 4.5 Hz, NMe), 2.93e3.09
(4H, m, N(CH2)2), 6.98 (1H, q, J 4.5 Hz, NH), 8.04 (1H, s,
CH), 8.18 (2H, br s, NH2); FABMS m/z: 249(Anþ2Hþ),
334(AnþCatþHþ); nmax (KBr) 1235, 1397, 1497, 1618,
1660, 2183, 2942, 3120, 3444. Purification caused decomposi-
tion of the salt that is why the CHN analysis was not
representative.
NMR) on a Varian Mercury VX-200 spectrometer in DMSO-
d6, using TMS as an internal standard (chemical shifts in parts
per million). IR spectra were taken on a Spectrum ONE spectro-
photometer in KBr pellet. Mass spectra were taken on a Varian
1200 L DIP; Ioniz. mode: EI; Electron energy: ꢀ70 eV. FAB
mass-spectrometric experiments were performed using mag-
netic sector mass spectrometer MI-1201E (‘SELMI’ Works,
Sumy, Ukraine) equipped with commercial FAB units; argon
was used as a bombarding gas, the energy of the primary
beam was 4.5 keV; the compounds were dissolved in m-NBA
matrix.
5.2. General procedure for the preparation of the
dimethylammonium 2-(2-carbamoyl-2-cyano-1-ethenyl)-5,5-
dimethyl-3-oxo-1-cyclohexen-1-olate (14b,c)
5.3.2. Hexahydropyridinium 2-(2-benzylcarbamoyl-2-
cyano-1-ethenyl)-5,5-dimethyl-3-oxo-1-cyclohexen-1-
olate (14f)
Yield 9.12 g, 62%; [Found: C, 70.4; H, 7.6; N, 10.0.
C24H31N3O3 requires C, 70.4; H, 7.6; N, 10.3%]; mp 145e
147 ꢁC; dH (200 MHz, DMSO-d6) 0.92 (6H, s, Me), 1.48e
1.68 (6H, m, (CH2)3), 2.10 (4H, s, CH2), 2.89e3.07 (4H, m,
N(CH2)2), 4.33 (2H, d, J 5.7 Hz, CH2), 7.17e7.32 (5H, m,
Ph), 7.58 (1H, t, J 5.7 Hz, NH), 8.08 (1H, s, CH); nmax
(KBr) 1229, 1271, 1394, 1485, 1534, 1603, 1618, 1655,
2187, 2955, 2932, 3345; FABMS m/z: 325 (Anþ2Hþ), 410
(AnþCatþHþ).
For the preparation of the enamine 12, a mixture of
dimedone 10 (5.00 g, 36.0 mmol) and DMFDMA (4.28 g,
36.0 mmol) was stirred for 5 min. Then 2-propanol (15 mL),
corresponding cyanacetamide 13 (36.0 mmol), and piperidine
(0.1 g, 0.11 mmol) were added consecutively to the reaction
mixture and stirred at room temperature for 5 h. A pale yellow
precipitate of the salt was formed, removed by filtration, washed
with ether, and dried.

S.A. Yermolayev et al. / Tetrahedron 64 (2008) 4649e4655
4653
5.3.3. Hexahydropyridinium 2-[2-cyano-2-(3-methylphenyl-
carbamoyl)-1-ethenyl]-5,5-dimethyl-3-oxo-1-cyclohexen-1-
olate (14h)
br s, NH2), 8.05 (1H, s, CH); nmax (KBr) 1284, 1352, 1487,
1557, 1665, 2182, 2958, 3173, 3358, 3484; FABMS m/z:
176 (NBAþCatþ), 257 (AnþCatþHþ), 279 (Anþ2Cat). The
CNH analysis of the sodium salts was not representative in
all cases.
Yield 7.36 g, 50%; [Found: C, 70.2; H, 7.8; N, 10.1.
C24H31N3O3 requires C, 70.4; H, 7.6; N, 10.3%]; mp 135e
137 ꢁC (dec); dH (200 MHz, DMSO-d6) 0.93 (6H, s, Me),
1.49e1.69 (6H, m, (CH2)3), 2.12 (4H, s, CH2), 2.24 (3H, s,
Me), 2.87e3.06 (4H, m, N(CH2)2), 6.80 (1H, d, J 7.8 Hz,
CH), 7.12 (1H, t, J 7.8 Hz, CH), 7.35e7.45 (2H, m, CH),
8.08 (1H, s, CH), 8.80 (1H, s, CH); nmax (KBr) 1230, 1300,
1368, 1396, 1484, 1545, 1606, 1642, 2193, 2725, 2857, 2955,
3033, 3322; FABMS m/z: 325 (Anþ2Hþ), 410(AnþCatþHþ).
5.4.2. Sodium 2-(-2-cyano-2-methylcarbamoyl-1-ethenyl)-
5,5-dimethyl-3-oxo-1-cyclohexen-1-olate (14d)
Yield 2.82 g, 29%; mp 250e253 ꢁC (dec); dH (200 MHz,
DMSO-d6) 0.92 (6H, s, Me), 2.08 (4H, s, CH2), 2.64 (3H, d,
J 4.6 Hz, NCH3), 6.98 (1H, br q, J 4.6 Hz, NH), 8.04 (1H, s,
CH); dC (50 MHz, DMSO-d6) 27.1, 28.9, 30.1, 52.1, 88.3,
110.0, 120.8, 145.4, 166.9, 192.7 (APT); nmax (KBr) 1268,
1415, 1506, 1567, 1628, 1651, 2180, 2866, 2951, 3390,
3444; FABMS m/z: 176 (NBAþCatþ), 249 (AnþHþ), 271
(AnþCatþHþ), 293 (Anþ2Cat). The CNH analysis of the
sodium salts was not representative in all cases.
5.3.4. Hexahydropyridinium 2-[2-cyano-2-(2-methoxyphen-
ylcarbamoyl)-1-ethenyl]-5,5-dimethyl-3-oxo-1-cyclohexen-
1-olate (14i)
Yield 8.57 g, 56%; [Found: C, 67.8; H, 7.7; N, 9.8.
C24H31N3O4 requires C, 67.7; H, 7.3; N, 9.9%]; mp 135e
137 ꢁC; dH (200 MHz, DMSO-d6) 0.93 (6H, s, Me), 1.50e
1.68 (6H, m, (CH2)3), 2.14 (4H, s, CH2), 2.91e3.07 (4H, m,
N(CH2)2), 3.87 (3H, s, OMe), 6.84e7.07 (3H, m, CH),
7.34e7.46 (2H, m, CH), 8.20 (1H, s, CH), 8.30 (1H, d, J
7.7 Hz, CH), 8.68 (1H, s, NH); nmax (KBr) 1415, 1460,
1534, 1602, 1647, 2176, 2531, 2858, 2957, 3385; FABMS
m/z: 341 (Anþ2Hþ), 426 (AnþCatþHþ).
5.4.3. Sodium 2-(2-benzylcarbamoyl-2-cyano-1-ethenyl)-
5,5-dimethyl-3-oxo-1-cyclohexen-1-olate (14g)
Yield 2.49 g, 20%; mp 164e166 ꢁC; dH (200 MHz, DMSO-
d6) 0.91 (6H, s, Me), 2.09 (4H, s, CH2), 4.32 (2H, d, J 6.0 Hz,
CH2), 7.20e7.30 (5H, m, Ph), 7.53 (1H, t, J 6.0 Hz, NH),
8.08 (1H, s, Ch); nmax (KBr) 1236, 1408, 1490, 1535, 1654,
2190, 2953, 3418; FABMS m/z: 176 (NBAþCatþ), 347
(AnþCatþHþ), 369 (Anþ2Cat). The CNH analysis of the
sodium salts was not representative in all cases.
5.3.5. Hexahydropyridinium 2-[2-cyano-2-(1,3-thiazol-2-
carbamoyl)-1-ethenyl]-5,5-dimethyl-3-oxo-1-cyclohexen-1-
olate (14j)
5.5. General procedure for the preparation of the 7,7-
dimethyl-2,5-dioxo-1-aryl-1,2,5,6,7,8-hexahydro-3-
quinolinecarboxamides (16aei) and 7,7-dimethyl-2,5-
dioxo-1-pyridyl-1,2,5,6,7,8-hexahydro-3-quinolinecarb-
oxamide (16j)
Yield 11.14 g (77%); [Found: C, 59.2; H, 6.5; N, 13.7; S,
7.9. C20H26N4O3S requires C, 59.7; H, 6.5; N, 13.9; S,
8.0%]; mp 156e158 ꢁC (dec); dH (200 MHz, DMSO-d6)
0.93 (6H, s, Me), 1.49e1.69 (6H, m, (CH2)3), 2.16 (4H, s,
CH2), 2.89e3.07 (4H, m, N(CH2)2), 7.12 (1H, d, J 3.6 Hz,
CH), 7.41 (1H, d, J 3.6 Hz, CH), 8.13 (1H, s, CH); nmax
(KBr) 1205, 1272, 1403, 1476, 1532, 1567, 1655, 2192,
2537, 2862, 2954, 3062, 3395; FABMS m/z: 318 (Anþ2Hþ),
403 (AnþCatþHþ).
Aromatic or heterocyclic amine 15 (7.2 mmol) was dissolved
in acetic acid (15 mL). An appropriate dialkylammonium or so-
dium 2-(2-carbamoyl-2-cyano-1-ethenyl)-5,5-dimethyl-3-oxo-
1-cyclohexen-1-olate 14 (6.6 mmol) was added to the solution
and stirred at room temperature for 10e15 min. Ayellow prod-
uct was formed after 5e15 min. Then water (15 mL) was
poured into the reaction mixture. The solid product was filtered
off, washed with water, and dried. Generally, the product ob-
tained in this manner had no additional signals in NMR spectra.
To prepare a sample for elemental analysis some products
needed to be recrystallized from solvent mentioned below.
5.4. A general procedure for the preparation of sodium 2-(2-
carbamoyl-2-cyano-1-ethenyl)-5,5-dimethyl-3-oxo-1-
cyclohexen-1-olates (14a,d,g)
Metallic sodium (0.92 g, 0.04 mol) was dissolved in anhy-
drous ethyl alcohol (90 mL). Corresponding cyanacetamide 13
(0.036 mol) was added to the solution of sodium ethoxide
and stirred for 10 min. The mixture was added to the enamine
12 obtained from dimedone 10 (5.00 g, 0.036 mol) and
DMFDMA (4.28 g, 0.036 mol). The reaction mixture was
stirred at room temperature for 30 min. A pale yellow precip-
itate was formed and removed by filtration, washed with ether,
and dried.
5.5.1. 1-(4-Diethylaminophenyl)-7,7-dimethyl-2,5-dioxo-
1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (16a)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14b. The product was
recrystallized from 1-butanol, yielding 1.84 g (73%); [Found:
C, 68.9; H, 6.9; N, 11.1, C22H27N3O3 requires C, 69.2; H, 7.1;
N, 11.0%]; mp 283e285 ꢁC (dec); dH (200 MHz, DMSO-d6)
0.93 (6H, s, Me), 1.11 (6H, t, J 7.0 Hz, N(CH2CH3)), 2.38
(2H, s, CH2), 2.46 (2H, s, CH2), 3.37 (4H, q, J 7.0 Hz,
N(CH2CH3)), 6.74 (2H, d, J 8.9 Hz, CH), 7.03 (2H, d,
J 8.9 Hz, CH), 7.65 (1H, s, NH), 8.56 (1H, s, NH), 8.76 (s,
5.4.1. Sodium 2-(2-carbamoyl-2-cyano-1-ethenyl)-5,5-
dimethyl-3-oxo-1-cyclohexen-1-olate (14a)
Yield 5.71 g, 62%; mp 190e192 ꢁC (dec); dH (200 MHz,
DMSO-d6) 0.91 (6H, s, Me), 2.09 (4H, s, CH2), 6.57 (2H,

4654
S.A. Yermolayev et al. / Tetrahedron 64 (2008) 4649e4655
1H, CH); nmax (KBr) 1406, 1519, 1607, 1674, 2970, 3357; MS
(EI) m/z: 381(Mþ), 367, 366, 380, 382, 349, 280, 321.
5.5.6. N3-(2-Methoxyphenyl)-7,7-dimethyl-1-(4-methylphe-
nyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinoline-
carboxamide (16f)
The title compound was obtained following the general pro-
cedure, using 6.6 mmol of enolate 14i. Yield 2.10 g (74%);
[Found: C, 72.6; H, 6.4; N, 6.5. C26H26N2O4 requires C, 72.5;
H, 6.1; N, 6.5%]; mp 267e269 ꢁC (dec); dH (200 MHz,
DMSO-d6) 0.93 (6H, s, Me), 2.42 (4H, s, CH2), 2.40 (3H, s,
Me), 3.78 (3H, s, OMe), 6.90e7.00 (1H, m, CH), 7.00e7.09
(2H, m, CH), 7.28 (2H, d, J 8.2 Hz, CH), 7.42 (2H, d,
J 8.2 Hz, CH), 8.47 (1H, d, J 8.1 Hz, CH), 8. 91 (1H, s, CH),
11.62 (1H, s, NH); nmax (KBr) 1525, 1597, 1672, 2923, 3506,
3594; MS (EI) m/z: 430 (Mþ), 309, 308, 254.
5.5.2. 7,7-Dimethyl-1-(4-nitrophenyl)-2,5-dioxo-1,2,5,6,7,8-
hexahydro-3-quinolinecarboxamide (16b)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14b. The product was
recrystallized from 1-butanol, yielding 1.41 g (60%); [Found:
C, 61.1; H, 5.0; N, 11.7, C18H17N3O5 requires C, 60.8; H, 4.8;
N, 11.8%]; mp 340e342 ꢁC (dec); dH (200 MHz, DMSO-d6)
0.93 (6H, s, Me), 2.37 (2H, s, CH2), 2.40 (2H, s, CH2),
7.67e7.77 (3H, m, CH and NH), 8.40 (1H, s, NH), 8.45
(2H, d, J 9.0 Hz, CH), 8.79 (1H, s, CH); dC (50 MHz,
DMSO-d6) 30.4, 35.3, 44.5, 52.2, 116.1, 122.1, 127.7, 132.5,
142.5, 145.5, 150.7, 161.6, 165.1, 166.2, 196.0; nmax (KBr)
1531, 1675, 3379, 3459; MS (EI) m/z: 355 (Mþ), 356, 340,
339, 312, 298, 283.
5.5.7. N3-Benzyl-1-(4-methoxyphenyl)-7,7-dimethyl-2,5-
dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (16g)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14f. Yield 2.52 g
(89%); [Found: C, 72.3; H, 6.3; N, 6.8. C26H26N2O4 requires
C, 72.5; H, 6.1; N, 6.5%]; mp 192e194 ꢁC; dH (200 MHz,
DMSO-d6) 0.92 (6H, s, Me), 2.39 (4H, s, CH2), 3.80 (3H, s,
OMe), 4.49 (2H, d, J 5.0 Hz, CH2), 7.10 (2H, d, J 8.9, CH),
7.20e7.34 (7H, m, CH and Ph), 8.79 (1H, s, CH), 9.59 (1H,
t, J 5.6 Hz, NH); nmax (KBr) 1509, 1680, 2960, 3057, 3296;
MS (EI) m/z: 430 (Mþ), 431, 413, 325, 324, 297, 254, 106.
5.5.3. 7,7-Dimethyl-1-(2-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-
hexahydro-3-quinolinecarboxamide (16c)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14b. The product was
recrystallized from 1-butanol, yielding 1.68 g (78%); [Found:
C, 70.6; H, 6.4; N, 9.0. C19H20N2O3 requires C, 70.4; H, 6.2;
N, 8.6%]; mp 262e264 ꢁC; dH (200 MHz, DMSO-d6) 0.92
(6H, d, J 6.7 Hz, Me), 1.98 (3H, s, Me), 2.07(1H, d,
J 18.2 Hz, CHaHb), 2.42 (2H, s, CH2), 2.52(1H, d, J 18.2 Hz,
CHaHb), 7.21e7.31 (1H, m, CH), 7.43 (3H, m, CH), 7.71
(1H, s, NH), 8.47 (1H, s, NH), 8.81 (1H, s, CH); nmax (KBr)
1535, 1688, 2951, 3131, 3334; MS (EI) m/z: 324 (Mþ), 325,
309, 307, 293, 292, 280.
5.5.8. N3,7,7-Trimethyl-1-(4-methoxyphenyl)-2,5-dioxo-
1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (16h)
The title compound was obtained following the general proce-
dure, using 6.6 mmol of enolate 14c. The product was recrystal-
lized from 1-butanol, yielding 1.80 g (77%); [Found: C, 67.5; H,
6.4; N, 8.0. C20H22N2O4 requires C, 67.8; H, 6.3; N, 7.9.]; mp
212e214 ꢁC; dH (200 MHz, DMSO-d6) 0.92 (6H, s, Me), 2.39
(4H, s, CH2), 2.78 (3H, d, J 4.5 Hz, NMe), 3.83 (3H, s, OMe),
7.11 (2H, d, J 9.4 Hz, CH), 7.27 (2H, d, J 9.4 Hz, CH), 8.77
(1H, s, CH), 9.07 (1H, q, J 4.5 Hz, NH); nmax (KBr) 1508, 1674,
2834, 2955, 3309; MS (EI) m/z: 354 (Mþ), 355, 324, 298, 297.
5.5.4. 2-(7,7-Dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexa-
hydro-3-quinolinylcarboxamido)-1,3-thiazole (16d)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14j. Yield 2.12 g
(82%); [Found: C, 64.1; H, 4.9; N, 11.1; S, 8.3.
C21H19N3O3S requires C, 64.1; H, 4.9; N, 10.7; S, 8.2%];
mp 293e295 ꢁC; dH (200 MHz, DMSO-d6) 0.94 (6H, s,
Me), 2.44 (4H, s, CH2), 7.31 (1H, d, J 3.6 Hz, CH), 7.40e
7.46 (1H, m, CH), 7.51 (1H, d, J 3.6 Hz, CH), 7.55e7.68
(3H m, CH), 8.91 (1H, s, CH), 12.58 (1H, s, NH); nmax
(KBr) 1522, 1637, 1678, 2953, 3061, 3429; MS (EI) m/z:
393 (Mþ), 295, 294, 238.
5.5.9. 1-(2-Aminophenyl)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-
hexahydro-3-quinolinecarboxamide (16i)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14b. The product was
recrystallized from 1-butanol, yielding 1.42 g (66%); [Found:
C, 66.4; H, 6.0; N, 13.1. C18H19N3O3 requires C, 66.5; H, 5.9;
N, 12.9%]; mp 273e275 ꢁC (dec); dH (200 MHz, DMSO-d6)
0.93 (6H, d, J 2.4 Hz, Me), 2.18 (1H, d, J 18.1 Hz, CHaHb),
2.34e2.44 (2H, m, CHaHb), 2.55 (1H, d, J 18.1 Hz, CHaHb),
5.37 (2H, s, NH2), 6.67 (1H, t, J 7.7 Hz, CH), 6.81 (1H, d,
J 8.2 Hz, CH), 6.99 (1H, d, J 7.7 Hz, CH), 7.16 (1H, t,
J 8.2 Hz, CH), 7.68 (1H, s, NH), 8.60 (1H, s, NH), 8.75 (1H,
s, CH); nmax (KBr) 1538, 1635, 1684, 2957, 3159, 3236,
3343, 3434; MS (EI) m/z: 325 (Mþ), 326, 308, 294, 293, 252.
5.5.5. 1-Phenyl-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexa-
hydro-3-quinolinecarboxamide (16e)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14b. Yield 1.51 g
(74%); [Found: C, 70.2; H, 5.9; N, 9.1. C18H18N2O3 requires
C, 70.0; H, 5.9; N, 9.0%]; mp 250e252; dH (200 MHz,
DMSO-d6) 0.91 (6H, s, Me), 2.36 (2H, s, CH2), 2.39 (2H, s,
CH2), 7.37 (2H, d, J 7.0 Hz, CH), 7.50e7.62 (3H, m, CH),
7.71 (1H, s, NH), 8.49 (1H, s, NH), 8.79 (1H, s, CH); nmax
(KBr) 3366, 2951, 1674, 1593, 1532.
5.5.10. 2-[7,7-Dimethyl-2,5-dioxo-1-(3-pyridyl)-1,2,5,6,7,8-
hexahydro-3-quinolinylcarboxamido]-1,3-thiazole (16j)
The title compound was obtained following the general
procedure, using 6.6 mmol of enolate 14j. The product was

S.A. Yermolayev et al. / Tetrahedron 64 (2008) 4649e4655
4655
recrystallized from 1-butanol, yielding 1.95 g (75%); [Found:
C, 61.2; H, 4.7; N, 14.2; S, 7.4. C21H19N3O3S requires C, 60.9;
H, 4.6; N, 14.2; S, 8.1%]; mp 264e266 ꢁC; dH (200 MHz,
DMSO-d6) 0.95 (6H, s, Me), 2.45 (4H, s, CH2), 7.32 (1H, d,
J 4.1 Hz, CH), 7.51 (1H, d, J 4.1 Hz, CH), 7.66e7.76 (1H,
m, CH), 7.99 (1H, d, J 9.2 Hz, CH), 8.68 (1H, s, CH), 8.79
(1H, d, J 4.9 Hz, CH), 8.91(1H, s, CH), 12.46 (1H, s, NH);
dC (200 MHz, DMSO-d6) 28.2, 33.0, 42.6, 49.8, 114.6,
115.0, 117.1, 125.3, 134.1, 136.4, 138.5, 141.1, 148.9,
151.0, 157.2, 160.7, 161.2, 163.4, 193.6 (APT); nmax (KBr)
1524, 1635, 1678, 2967, 3421; MS (EI) m/z: 394 (Mþ), 296,
295, 239.
graphic parameters have been deposit to the Cambridge Crys-
tallographic Data Centre (CCDC 676522).
References and notes
1. Gadekar, S. M. DE Patent 2,555,411, 1976; Chem. Abstr. 1976, 85,
198163b.
2. Qian, L.; Ji, R. Tetrahedron Lett. 1989, 16, 2089.
3. Bai, D. L.; Tang, X. C.; He, X. C. Curr. Med. Chem. 2000, 7, 355.
4. Gupta, A. K.; Kohli, Y. Br. J. Dermatol. 2003, 149, 296.
5. Presti, E. L.; Boggia, R.; Feltrin, A.; Menozzi, G.; Dorigo, P.; Mosti, L.
Farmaco 1999, 54, 465.
6. Matsumori, A.; Ono, K.; Sato, Y.; Shioi, T.; Nose, Y.; Sasayama, S. J. Mol.
Cell. Cardiol. 1996, 28, 2491.
7. De Clercq, E. Farmaco 1999, 54, 26.
8. Parreira, R. L. T.; Abrahao, O.; Galembeck, S. E. Tetrahedron 2001, 57,
3243.
5.6. X-ray diffraction study
9. Eastland, G. Drugs Future 1986, 11, 99.
Crystals of 14h are monoclinic. At 293 K a¼13.276(6),
10. Snider, B. B.; Lu, Q. J. Org. Chem. 1994, 59, 8065.
11. Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
12. Gorobets, N. Yu.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron
2004, 60, 8633.
3
ꢁ
˚
˚
b¼17.181(5), c¼10.440(2) A, b¼96.45(2) , V¼2366(1) A ,
Mr¼409.52, Z¼4, space group P21/c, dcalcd¼1.150 g/cm3,
m(Mo Ka)¼0.076 mmꢀ1, F(000)¼880.
13. Eiden, F.; Herdeis, C. Arch. Pharm. 1978, 311, 287.
14. Mosti, L.; Schenone, P.; Menozzi, G. J. Heterocycl. Chem. 1985, 22, 1503.
15. Sacquet, M.-C.; Maitte, P. J. Heterocycl. Chem. 1985, 22, 713.
16. Bondavalli, F.; Bruno, O.; Presti, E. L.; Menozzi, G.; Mosti, L. Synthesis
1999, 7, 1169.
Crystals of 16e are triclinic. At 100 K a¼8.473(1), b¼
ꢁ
ꢁ
˚
˚
9.128(2), c¼12.145(1) A, a¼103.52(2) , b¼93.31(1) , g¼
3
116.96(2), V¼799.4(2) A , Mr¼310.34, Z¼2, space group
P1, dcalcd¼1.289 g/cm3, m(Mo Ka)¼0.089 mmꢀ1, F(000)¼
17. Krasnaya, Zh. A.; Stytsenko, T. S.; Prokofev, E. P.; Kucherov, V. F. Izv.
Akad. Nauk SSSR, Ser. Khim. 1973, 11, 2543; Chem. Abstr. 1974, 80,
59832.
328.
Intensity of 9613 reflections (4066 independent, Rint¼0.037)
for 14h and intensity of 5939 reflections (2798 independent,
Rint¼0.018) for 16e were measured on the ‘Xcalibur-3’ diffrac-
tometer (graphite monochromated Mo Ka radiation, CCD
detector, u-scaning, 2Qmax¼50ꢁ). Both structures were solved
by direct method using SHELXTL package.28 Positions of
hydrogen atoms were located from electron density difference
maps and refined using isotropic approximation. Full-matrix
least-squares refinement against F2 in anisotropic approxima-
tion for non-hydrogen atoms of 14h using 4047 reflections
was converged to wR2¼0.107 (R1¼0.044 for 2340 reflections
with F>4s(F), S¼0.854). Atomic coordinates and crystallo-
graphic parameters have been deposit to the Cambridge
Crystallographic Data Centre (CCDC 676521). Full-matrix
least-squares refinement against F2 in anisotropic approxima-
tion of 16e for non-hydrogen atoms using 2726 reflections
was converged to wR2¼0.092 (R1¼0.036 for 2285 reflections
with F>4s(F), S¼1.050). Atomic coordinates and crystallo-
18. Ziegler, E.; Wolfbeis, O. Z. Naturforsch. 1976, 31B, 1519.
19. Trummer, I.; Ziegler, E.; Wolfbeis, O. S. Synthesis 1981, 3, 225.
20. Gelin, R.; Makula, D. Bull. Soc. Chim. Fr. 1968, 3, 1129.
21. Ryabova, S. Y.; Alekseeva, L. M.; Granik, V. G. Chem. Heterocycl.
Compd. 1991, 9, 960.
22. Ryabova, S. Yu.; Trofimkin, Yu. I.; Alekseeva, L. M.; Khabarova, L. S.;
Granik, V. G. Chem. Heterocycl. Compd. 1991, 3, 278.
23. Wipfler, H.; Ziegler, E.; Wolfbeis, O. Z. Naturforsch. 1978, 33B, 1016.
24. Abu-Shanab, F. A.; Redhouse, A. D.; Thompson, J. R.; Wakefield, B. J.
Synthesis 1995, 557.
25. Collins, I.; Moyes, C.; Davey, W. B.; Rowley, M.; Bromidge, F. A.; Quirk,
K.; Atack, J. R.; McKernan, R. M.; Thompson, S.-A.; Wafford, K.;
Dawson, G. R.; Pike, A.; Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro,
J. L. J. Med. Chem. 2002, 45, 1887.
26. Ried, W.; Schleimer, B. Angew. Chem. 1958, 70, 164.
27. Burgi, H.-B.; Dunitz, J. D. Structure Correlation; VCH: Weinheim, 1994;
Vol. 2, pp 741e784.
28. Sheldrick G. M. SHELXTL PLUS. PC Version. A System of Computer Pro-
grams for the Determination of Crystal Structure from X-ray Diffraction
Data. Rev. 5.1, 1998.