Pathways for cyclizations of hydrazine-derived 2-(2-cyanovinyl)-3-oxo- cyclohex-1-ene enolates

Article abstract of DOI:10.1016/j.tet.2011.02.052

The introduction of a hydrazine functionality into 2-(2-cyanovinyl)-3-oxo- cyclohex-1-ene enolates results in their spontaneous cyclizations with participation of the hydrazine moiety. Depending on the reaction conditions used, the hydrazine-derived enola

Full text of DOI:10.1016/j.tet.2011.02.052

Tetrahedron 67 (2011) 2934e2941
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Pathways for cyclizations of hydrazine-derived 2-(2-cyanovinyl)-
3-oxo-cyclohex-1-ene enolates
,
,
a
a
Sergey A. Yermolayeva b, Nickolay Yu. Gorobets a , Oleg V. Shishkin , Svetlana V. Shishkina ,
*
Nicholas E. Leadbeater b
a SSI ‘Institute for Single Crystals’ of National Academy of Science of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine
b Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, 06269-3060 CT, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2010
Received in revised form 31 January 2011
Accepted 21 February 2011
Available online 26 February 2011
The introduction of a hydrazine functionality into 2-(2-cyanovinyl)-3-oxo-cyclohex-1-ene enolates re-
sults in their spontaneous cyclizations with participation of the hydrazine moiety. Depending on the
reaction conditions used, the hydrazine-derived enolates are transformed into derivatives of 1-arylpyr-
idine-2-one-3-carbonitriles or pyrazoloquinolinones in a one-pot synthesis. They also react with anilines
to give the corresponding N1-substituted pyridine-2-one-3-carboxamides. Product characterization was
performed by means of spectroscopic and X-ray diffraction studies. In addition, for structure elucidation
purposes, a counter synthesis of 1-arylaminopyridine-2-one-3-carboxamide was also carried out.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Pyridones
Enolates
One-pot synthesis
1. Introduction
of 2-pyridone or 2-pyranone derivatives.9e12 In spite of obvious
synthetic potential of these salts, their application as starting ma-
The development of novel methods for the synthesis of 2-pyr-
idone derivatives1 is of interest due to the fact that a number of
compounds in this class exhibit interesting biological activities.2,3
Namely, some 2-pyridone derivatives possess antiphlogistic (pir-
fenidone 1, Scheme 1),4 antiulcer,5 and antifungal6 activities. Well
known inotropic agents milrinone 27 and amrinone7 also contain
the 2-pyridone moiety. In the last decade, considerable attention
has been also focused on investigation of nucleosides analogs 3
serving as valuable tools in structure activity studies.8
terials for the synthesis of 2-pyridone derivatives and other het-
erocycles has not been widely studied.
We have previously described several methods for the synthesis
of 2-pyridone derivatives by means of reactive intermediate eno-
lates 4 (Scheme 2).13e16 These enolates are highly functionalized
and it was possible to switch on the reactivity of their cyano and
amide groups selectively for the 2-pyridone ring construction
depending on the reaction conditions used. Heating of the enolates
4 in 2-propanol leads to the formation of 2-pyridones 5. Probably
this transformation takes place via the intermediate formation of
an iminopyrane cycle, which is highly labile and forms 2-pyridones
5 via Dimroth-like rotation.13 Use of basic reaction media activates
the amide function of the enolates 4 resulting in the formation of
N1-substituted 2-pyridines-3-carbonitriles 7.15 On the other hand,
under acidic conditions enolates 4 react with amines forming N1-
substituted 2-pyridines-3-carbonitriles 6.14
H3C
O
N
NH
CN
O
N
O
HO
R
Me
N
H
O
OH
2
1
3
The subsequent isolation of the salts 4 was very helpful for
understanding of the mechanism of these transformations and
now for the application of these salts as reactive building blocks
for further transformations. Here we report the continuation of
our study into the synthetic potential of the enolates, broadening
the horizons of their reactivity by introduction of an additional
reaction center; namely a hydrazine-type nitrogen, into the am-
ide group.
Scheme 1.
Enolates containing the 4-cyano-1,3-butadienolate moiety are
usually formed as intermediates or byproducts during the synthesis
* Corresponding author. Fax: þ38 (572) 3409343; e-mail address: gorobets@
isc.kharkov.com (N.Yu. Gorobets).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.052

S.A. Yermolayev et al. / Tetrahedron 67 (2011) 2934e2941
2935
O
NMe2
1
R
MeO
OMe
O
2
R
+
3
CONHR
CN
one pot
O
O
O
3
CONHR
3
CN
O
CONHR
1
1
R
R
1
CN
R
-
N
N
O
2
O
2
2
R
+
Cat
R
R
3
H
R
5
4
7
ArNH2
1
R = H, Me
O
2
R = H, Me, Ar, Het
3
CONHR
3
R = H, Alk, Ar, Het
1
R
+
+
+
Cat =
+
N
O
H2NMe2, H2N
, Na
2
R
Ar
6
Scheme 2. Previous research on the reactivity of 2-(2-cyanovinyl)-3-oxo-cyclohex-1-ene enolates 4.
2. Results and discussion
dimethylformamide dimethylacetal (DMF-DMA), the process being
complete within a few minutes at room temperature. Then, the
appropriate substituted 2-cyanoacetohydrazide 8 is added to the
formed enamine 11 along with 2-propanol and 1 equivof piperidine.
After stirring for 30 min at room temperature the solid product 9 is
separated as precipitate and removed upon filtration (Scheme 4). As
cyclic 1,3-dicarbonyl compounds, cyclohexanediones 10aed and N-
Boc-piperidinedione 10e were used. With the exception of com-
mercially available dimedone, these compounds were synthesized
by known methods.18,19 Attempts to synthesize enolates with acyclic
1,3-dicarbonyl compounds under such conditions, however, were
not successful. The reason for this could be associated with the en-
hanced conjugation of negative charge in the cyclic enoles due to the
higher acidity of the cyclic 1,3-dicarbonyl compounds as compared
to their acyclic analogs.20,21
The starting active methylene nitriles 8aed bearing the hydra-
zine function were synthesized following a known procedure by
the reaction of an in situ formed cyanoacetylazide with commer-
cially available arylhydrazines (Scheme 3).17
O
O
O
H
R'NHNH2
NaNO2
HCl
NH2
N
N
R'
N
N3
H
H
CN
CN
CN
8a-d
Scheme 3. Synthesis of starting nitriles 8aed (isolated yield):
b R0¼R0¼4-FePh (48%); c 4-CO2MeePh (57%); d R0¼3-MeePh (56%).
a
R0¼Ph (50%);
The enolates 9aec obtained were readily soluble in water, this
meaning that aqueous conditions could be used for their further
transformation. After heating at 80 ꢀC for 5 min in water, enolates
9aec could be cyclized to give the corresponding 3-cyano-2-pyr-
idones 12aec (Scheme 5, Table 1). Interestingly, in the case of the
The previous procedure14 used for the preparationof enolates 4 is
generally suitable also for the synthesis of their hydrazine
derivatives 9. It consists of two steps carried out in one pot:
initially the cyclic 1,3-dicarbonyl compound 10 is reacted with neat
O
H
H
O
N
O
R
N
R'
O
R
O
R
N
R'
N
H
DMFDMA
8a,b
CN
H
R
R
NMe2
R
CN
i-PrOH
neat
-
+
O
O
O
H2N
piperidine
9a-c
11
10a-e
O
O
O
O
O
Boc
N
Me
O
O
O
Ph
O
O
Me
10a
O
Cl
10b
10d
10c
10e
Scheme 4. Hydrazine-derived enolates 9aec (isolated yield): a ReR¼eCH2CMe2CH2e, R0¼Ph (70%); b ReR¼eCH2CMe2CH2e, R0¼4-FePh (82%); c ReR¼eN(Boc)CH2CH2e, R0¼Ph
(69%).

2936
S.A. Yermolayev et al. / Tetrahedron 67 (2011) 2934e2941
O
O
H
N
N
Ph
Me
H
N
O
Me
R"
15
O
R
CN
O
H2O
HOAc
ArNH2
R
NMe2
OMe
N
MeO
O
HN R'
NH
HN
O
R
R'
O
R
12
R
+
R
O
CN
H
N
O
O
N
R'
O
OH
N
NH2Alk2
H
CN
9
R
HOAc
N
HOAc
R
N
R'
13
HO
O
N
N
R
R'
NH
R
OH
14
Scheme 5.
Table 1
method gave significantly higher overall yields in comparison with
the stage-by-stage method. Applying this method the range of
3-cyano-2-pyridones 12aek was synthesized with good overall
yields (Table 1). Piperidine (1 equiv) proved essential in this cycli-
zation. Lower loadings of piperidine caused side reactions, thereby
increasing the quantities of impurities.
Changing the solvent from water to acetic acid yielded different
products, namely the 1H-pyrazolo[3,4-b]pyridin-3-ol derivatives
13aed (Scheme 5). In this case, the hydrazine-type nitrogen par-
ticipated in the cyclization with the cyano group, forming the
iminopyrozoline intermediate 14, which is then transformed into
the corresponding 1H-pyrazolo[3,4-b]pyridin-3-ol 13. Overall
yields of this transformation were modest, a number of byproducts
also being formed. However, the pyrazolo[3,4-b]pyridin-3-ols
13aed had the lowest solubility in acetic acid providing a simple
method for their separation.
To complete the comparative investigation of chemical proper-
ties of enolates 4 and 9, the reactivity of 9aec reacted with anilines
was probed. In this case no significant differences were observed.
The corresponding N1-substituted 2-pyridones 15aec were
obtained in good yields (Scheme 4, Table 1).
During the synthesis of compounds 12 and 13 the formation of
small quantities of a compound with the presumed structure of
N1-unsubstituted 2-pyridone 16 was observed (Scheme 6).22 At-
tempts were made to synthesize these interesting products in
The yields for compounds 12aek, 13aed, and 16aec
Compounds ReR
R0
R00
Yielda
12a
12b
12c
12d
12e
eCH2C(CH3)CH2e
C6H5
4-FeC6H4
C6H5
3-CH3eC6H4
4-COOMee
C6H4
4-FeC6H4
C6H5
d
d
d
d
d
65% (45%b)
80% (62%b)
50% (26%b)
41%
eCH2C(CH3)CH2e
eN(Boc)CH2CH2e
eCH2C(CH3)2CH2e
eCH2C(CH3)2CH2e
64%
12f
12g
12h
12i
eN(Boc)CH2CH2e
d
d
d
d
d
d
d
d
d
d
72%
64%
50%
45%
54%
44%
eCH2CH(Furyl)CH2e
eCH2CH(C6H5)CH2e
eCH2CH(C6H5)CH2e
C6H5
4-FeC6H4
12j
eCH2CH(4-ClC6H4)CH2e C6H5
eCH2CH(4-ClC6H4)CH2e 4-FeC6H4
12k
13a
13b
13c
13d
15a
15b
15c
eCH2C(CH3)2CH2e
eCH2C(CH3)2CH2e
eCH2C(CH3)2CH2e
eCH2CH(Furyl)CH2e
eCH2C(CH3)2CH2e
eCH2C(CH3)2CH2e
eCH2C(CH3)2CH2e
C6H5
36% (28%b)
37%
3-CH3eC6H4
4-FeC6H4
C6H5
C6H5
C6H5
34% (26%b)
11%
4-FeC6H4
3-CleC6H4
64%c
60%c
C6H5
2-MeOeC6H4 63%c
a
Isolated yields over three steps.
Isolated yields of the pyridones synthesis with separation of the enolates 9
b
calculated over three steps.
c
Isolated yields calculated on the amount of the starting salt 9a.
corresponding enolates bearing an amide group instead of a hy-
drazide group, the cyclization required a higher temperature
(120 ꢀC) and longer time (10 min) in order to obtain acceptable
yields of product.15 This is probably associated with the increase in
nucleophilicity of the amide nitrogen influenced by the neighbor-
ing nitrogen in enolates 9; the so-called alpha-effect.
Issues with isolation of 9aec cause the yields to decrease during
the work-up stages. As a result, attempts were made to convert
them into the desired 3-cyano-2-pyridones 12aec in one pot
without separation of the enolates. This one-pot, three-step
O
O
O
O
R
H
CN
N
N
Ph
R
O
Me
Me
H
NH
N
N
H
R'
17
16
Scheme 6.

S.A. Yermolayev et al. / Tetrahedron 67 (2011) 2934e2941
2937
3. Structure elucidation
Besides 3-cyano-2-pyridone 12 and 1H-pyrazolo[3,4-b]pyridin-
3-ol 13, formation of diazepinone 17 (Scheme 6) was also possible.
For this reason, considerable attention was focused on structure
determination for these compounds. All the compounds have the
same molecular weight and set of protons complicating structure
elucidation by means of mass and 1H NMR spectroscopy. Attempts
to prove the structures of the obtained compounds by means of
correlation NMR spectroscopy (NOESY, HMBC, and HMQC) were
not successful. The structure of compound 13a was proven by
means of X-ray analysis (Fig. 1).
Unfortunately, X-ray analysis for compounds 12 could not be
performed since a single crystal of suitable quality could not be
successfully grown. However, the related compounds 18aec
could be easily synthesized by the reaction of the salts 4a with
corresponding hydrazine hydrochlorides 19aec (Scheme 7)
similarly to compounds 15aec (Scheme 5) using water as a sol-
vent. The structure of 18c was unequivocally determined by
means of single crystal X-ray analysis (Fig. 2). In the 1H NMR
spectra, the coupling profiles of the methylene groups for
compounds 12 and 18 were very similar. That is why we
attempted to convert the nitriles 12 into the amides 18 to prove
definitively the structure of compound 12. An acceptable pro-
tocol for this conversion was a palladium-catalyzed trans-
formation of nitriles into amides by the action of acetamide
excess (Scheme 6).23
Fig. 1. The molecular structure of 13a. The atom numbering corresponds to that in X-
ray analysis data.
greater amounts by variation of the reaction conditions, but in all
cases, compounds 12 and 13 predominated. The reason for these
difficulties is the high nucleophilicity of hydrazine group, causing it
to react faster with cyano or enol groups (Scheme 5) than Dimroth-
like rotation proceeds (Scheme 2).
O
O
O
O
CN
O
O
NH2
NHNH3+Cl-
NH2
Me
Me
i
H2O
N
+
CN
Me
Me
N
O
Me
R
Me
NH
O
NH
NH2Me2
R
19a-c
4a
12a
18a-c
R: a) C6H5; b) 3-CH3-C6H4;
c) 2,4-diMe-C6H3
Scheme 7. i: Acetamide (10 equiv), PdCl2 (10 mol %), durene (30 mol %), reflux in dioxane for 40 h, 30% conversion.
4. Conclusions
The addition of the hydrazine-type nitrogen into the amide group
of 2-(2-cyanovinyl)-3-oxo-cyclohex-1-ene results in particular
changes of their reactivity. The formation of 2-pyridone ring of com-
pounds 12 with participation of the acylated hydrazine nitrogen of
enolates 9 proceeds easier than for derivatives 4: at lower tempera-
ture in water and without addition base. In this case, the neighboring
nitrogen atom increases thenucleophilicityof the amide nitrogen due
to the alpha-effect. Employing acetic acid as the solvent probably
prevents the reaction of acylated hydrazine nitrogen, and the arylated
nitrogen appears to be more reactive under these conditions. In this
waytheinitialattackof thearylatedhydrazinenitrogenproceedswith
sequential formation of iminopyrozoline intermediate 14 and
1H-pyrazolo[3,4-b]pyridin-3-ol 13. At the same time, the presence of
the amide nitrogen does not prevent the reaction of enolates 9 with
anilines in acetic acid to give N1-substituted 2-pyridones 16.
5. Experimental
5.1. General
1H NMR and 13C NMR spectra were recorded on Bruker DRX-400
(400 MHz) or Bruker DRX-300 (300 MHz) spectrometers in DMSO-
d6 and chemical shifts (d) are expressed in parts per million relative
to TMS as an internal standard. High resolution mass spectra were
Fig. 2. The molecular structure of 18c. The atom numbering corresponds to that in
X-ray analysis data.
recorded with Q-TOF mass spectrometer operating in ESIþ mode

2938
S.A. Yermolayev et al. / Tetrahedron 67 (2011) 2934e2941
unless otherwise indicated. Starting materials were obtained from
commercial suppliers and used without further purification. The
enolate 4a was synthesized by the described method.13
2-propanol was added the requisite hydrazide 8 (1.3 mmol) and
piperidine (120 g, 1.4 mmol). The mixture was stirred for
10e30 min at room temperature until a pale yellow precipitate of
the salt 9 was formed. Then, water (2 mL) was added, this dis-
solving enolate 9, and then reaction mixture was placed into heated
oil bath and refluxed for 5 min. After heating, the 2-propanol sol-
vent was almost completely evaporated and an oily residue was
left. After cooling the residue crystallized. The product was filtered
and dried under vacuum. In most cases the product did not require
additional purification. Recrystallization of the crude product using
a mixture of 2-propanol and water (2:1) was used if needed.
5.2. Preparation of cyano-acetic acid N0-aryl-hydrazides 8
Cyano-acetic acid hydrazide (5.64 g, 57 mmol) was dissolved in
water (20 mL) and acidified using concentrated hydrochloric acid
(4.8 mL). Themixturewascooledto0ꢀCanddiethylether(20 mL)was
added. A solution of sodium nitrite (3.86 g, 56 mmol in 7 mL of water)
was added dropwise over the period of 15 min to the mixture of hy-
drazide hydrochloride, maintaining the temperature below 5 ꢀC and
using vigorous stirring. After complete addition of the sodium nitrite,
the reaction mixture was stirred for an additional 30 min at the same
temperature. The corresponding arylhydrazine (0.056 mmol) was
added to the solution of formed azide and the reaction mixture was
stirred for an additional hour. Application of hydrazines hydrochlo-
rides requires neutralization by sodium hydroxide and neutralized
solution can be used in the reaction with azide.
5.4.1. 7,7-Dimethyl-2,5-dioxo-1-phenylamino-1,2,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (12a). Yield: 260 mg, 65%; mp: 175e177 ꢀC;
1H NMR (300 MHz, DMSO-d6)
d
1.02 (s, 6H), 2.50 (d, J¼9.0 Hz, 2H),
2.79 (d, J¼18.0 Hz,1H), 3.23 (d, J¼18.0 Hz,1H), 6.70 (d, J¼8.0 Hz, 2H),
6.91 (t, J¼8.0 Hz, 1H), 7.24 (t, J¼8.0 Hz, 2H), 8.56 (s, 1H), 9.36 (s, 1H);
13C NMR (100 MHz, DMSO-d6)
d 27.5, 37.8, 38.9, 39.5, 48.8, 99.3,
101.6,112.6,115.0,120.9,129.1,143.8,145.5,158.9,164.5,192.4; HRMS
(ESI) calculated for C18H18N3O2 (MþHþ) 308.1399; found, 308.1420;
IR (KBr), cmꢁ1: 1538, 1641, 1671, 2230, 2959, 3259.
The precipitated cyano-acetic acid N0-aryl-hydrazide was fil-
tered off, washed with 5 mL of water and then with 5 mL of ether.
For additional purification recrystallization in water or in etha-
nolewater mixture (1:1) can be used.
5.4.2. 1-(4-Fluoro-phenylamino)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-
hexahydro-quinoline-3-carbonitrile (12b). Yield: 338 mg, 80%; mp:
5.3. General procedure for the synthesis of enolates 9
175e177 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
1.03 (s, 6H), 2.47 (br s,
2H), 2.85 (br s, 1H), 3.21 (br s, 1H), 6.69e6.79 (m, 2H), 7.03e7.14 (m,
2H), 8.54 (s,1H), 9.32 (br s,1H); 13C NMR (100 MHz, DMSO-d6)
28.4,
The corresponding methylenactive 1,3-dicarbonyl compound 10
(1.4 mmol) was mixed with DMF-DMA (1.4 mmol) and stirred for
5 min at room temperature. The resulting enamine 11 was diluted
with 2-propanol (1 mL). To the solution of enamine 11 in 2-prop-
anol was added the requisite hydrazide 8 (1.3 mmol) and piperidine
(0.119 g, 1.4 mmol). The mixture was stirred for 10e30 min at room
temperature until a pale yellow precipitate of the salt 9 was formed.
The precipitate was filtered, washed with diethyl ether (5 mL), and
dried at room temperature. The obtained pale yellow compound
did not require additional purification.
d
28.6, 32.8, 49.9, 113.3, 115.0, 116.5, 126.6, 139.8, 143.3, 162.1, 163.0,
164.2, 194.3; HRMS (ESI) calculated for C18H16N3O2FNa (MþNaþ)
348.1124; found, 348.1069; IR (KBr), cmꢁ1: 1507, 1534, 1671, 2230,
2891, 2964, 3270, 3380.
5.4.3. 3-Cyano-2,5-dioxo-1-phenylamino-1,5,7,8-tetrahydro-2H-
[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (12c). Yield:
247 mg, 50%; mp: 156e158 ꢀC (dec); 1H NMR (300 MHz, DMSO-d6)
d
1.49 (s, 9H), 2.91e3.11 (m, 1H), 3.26e3.47 (m, 1H), 3.79e4.07 (m,
2H), 6.73 (d, J¼8.0 Hz, 2H), 6.91 (t, J¼7.3 Hz, 1H), 7.23 (d, J¼7.3 Hz,
2H), 8.62 (s, 1H), 9.38 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
24.8,
5.3.1. Piperidinium 2-[2-cyano-2-(N0-phenyl-hydrazinocarbonyl)-vi-
d
nyl]-5,5-dimethyl-3-oxo-cyclohex-1-enate (9a). Yield: 430 mg, 70%;
25.0, 27.1, 82.0, 101.4, 108.5, 111.6, 112.6, 114.7, 120.7, 128.7, 145.2,
151.4, 158.1, 159.5, 161.6; HRMS (ESI) calculated for C20H20N4O4Na
(MþNaþ) 403.1382; found, 403.1383; IR (KBr), cmꢁ1: 1671, 1689,
1715, 1759, 2233, 3049, 3260.
mp: 154e156 ꢀC (dec); 1H NMR (300 MHz, DMSO-d6)
d 0.95 (s, 6H),
1.49e1.71 (m, 6H), 2.13 (s, 4H), 2.94e3.06 (m, 4H), 6.62e6.75 (m,
3H), 7.12 (t, J¼8.0 Hz, 2H), 7.59 (s, 1H), 8.06 (s, 1H), 8.91 (s, 1H); 13C
NMR (100 MHz, DMSO-d6)
d 22.4, 23.0, 29.1, 31.1, 44.5, 52.4, 86.4,
100.2, 110.8, 112.9, 118.9, 120.0, 129.2, 146.1, 150.5, 167.5, 192.9.
5.4.4. 7,7-Dimethyl-2,5-dioxo-1-m-tolylamino-1,2,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (12d). Yield: 171 mg, 41%; mp: 166e168 ꢀC;
5.3.2. Piperidinium 2-{2-cyano-2-[N0-(4-fluoro-phenyl)-hydrazinoca
rbonyl]-vinyl}-5,5-dimethyl-3-oxocyclohex-1-enolate(9b). Yield:486
1H NMR (300 MHz, DMSO-d6)
d 1.00 (s, 6H), 2.21 (s, 3H), 2.45 (s, 2H),
2.76(d, J¼13.0 Hz, 2H), 3.21 (d, J¼13.0 Hz,1H), 6.39e6.54(m, 2H), 6.71
mg, 82%; mp: 154e156 ꢀC (dec); 1H NMR (300 MHz, DMSO-d6)
d 0.95
(d, J¼8.0 Hz, 2H), 7.09 (t, J¼8.0 Hz, 1H), 8.53 (s, 1H), 9.23 (s, 1H); 13C
(s, 6H), 1.49e1.70 (m, 6H), 2.13 (s, 4H), 2.94e3.07 (m, 4H), 6.64e6.77
(m, 2H), 6.89e7.03 (m, 2H), 7.57 (s, 1H), 8.06 (s, 1H), 8.97 (s, 1H).
NMR (100 MHz, DMSO-d6) d 20.7, 25.1, 31.6, 38.5, 48.6, 101.4, 109.5,
112.4, 112.9, 114.8, 121.5, 128.7, 138.3, 143.6, 145.2, 158.6, 164.3, 192.2;
HRMS (ESI) calculated for C19H19N3O2Na (MþNaþ) 344.1375; found,
344.1366; IR (KBr), cmꢁ1: 1639, 1678, 2227, 2870, 2952, 3048, 3271.
5.3.3. Piperidinium 1-tert-butoxycarbonyl-5-[2-cyano-2-(N0-phenyl-
hydrazinocarbonyl)-vinyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-olate
(9c). Yield: 433 mg, 69%; mp: 149e151 ꢀC (dec); 1H NMR (300 MHz,
5.4.5. 4-(3-Cyano-7,7-dimethyl-2,5-dioxo-5,6,7,8-tetrahydro-2H-
DMSO-d6)
d
1.45 (s, 9H),1.52e1.60 (m, 2H),1.60e1.69 (m, 4H), 2.28 (t,
quinolin-1-ylamino)-benzoic acid methyl ester (12e). Yield: 388 mg,
J¼6.0 Hz, 2H), 2.99e3.02 (m, 4H), 3.64 (t, J¼6.0 Hz, 2H), 6.63e6.75
(m, 3H), 7.12 (t, J¼7.0 Hz, 2H), 7.60 (s, 1H), 8.16 (s,1H), 8.20 (br s, 2H),
8.96 (s, 1H).
64%; mp: 217e219 ꢀC (dec); 1H NMR (300 MHz, DMSO-d6)
d 0.99 (s,
6H), 2.45 (s, 2H), 2.72 (d, J¼19.0 Hz, 2H), 3.17 (d, J¼19.0 Hz,1H), 3.78
(s, 3H), 6.77 (d, J¼9.0 Hz, 2H), 6.82 (d, J¼9.0 Hz, 2H), 8.54 (s,1H), 9.72
(br s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 27.1, 27.4, 31.6, 48.5, 51.3,
5.4. General procedure for the synthesis of 2-pyridone-3-
carbonitiles 12
101.6, 111.8, 112.7, 114.7, 121.5, 130.5, 143.9, 149.6, 158.4, 164.2, 165.4,
192.1; HRMS (ESI) calculated for C20H19N3O4Na (MþNaþ) 388.1273;
found, 388.1260; IR (KBr), cmꢁ1: 1646,1675,1709, 2230, 2952, 3263.
The corresponding methylenactive 1,3-dicarbonyl compound 7
(1.4 mmol) was mixed with DMF-DMA (1.4 mmol) and stirred for
5 min at room temperature. The resulting enamine 11 was diluted
with 2-propanol (1 mL). To the solution of enamine 11 in
5.4.6. 3-Cyano-1-(4-fluoro-phenylamino)-2,5-dioxo-1,5,7,8-tetrahydro-
2H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (12f). Yield:
310 mg, 60%; mp: 193e195 ꢀC (dec); 1H NMR (300 MHz, DMSO-d6)

S.A. Yermolayev et al. / Tetrahedron 67 (2011) 2934e2941
2939
d
1.49 (s, 9H), 2.95e3.47 (m, 2H), 3.80e4.03 (m, 2H), 6.73e6.84 (m,
2H), 7.00e7.11 (m, 1H), 8.61 (s, 1H), 9.35 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) 25.3, 27.6, 41.6, 48.8, 82.4, 101.8, 108.9, 112.0, 113.0, 115.0,
piperidine (120 mg, 1.4 mmol). The mixture was stirred for
10e30 min at room temperature until a pale yellow precipitate of
the salt 9 was formed. Following this, acetic acid (1 mL) was added
and the reaction mixture placed into heated oil bath and refluxed for
5 min. The product precipitated during heating or after cooling. The
precipitate was filtered, washed with water, and then dried under
vacuum. In most cases further purification was not necessary.
d
121.1, 129.0, 145.6, 145.9, 151.8, 158.5, 160.0, 162.1; HRMS (ESI) calcu-
lated for C20H19N4O4NaF (MþNaþ) 421.1288; found, 421.1335; IR
(KBr), cmꢁ1: 1670, 1690, 1758, 2230, 2913, 2978, 3048, 3217, 3257.
5.4.7. 7-Furan-2-yl-2,5-dioxo-1-phenylamino-1,2,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (12g). Yield: 287 mg, 64%; mp: 112e114 ꢀC
5.5.1. 3-Hydroxy-7,7-dimethyl-1-phenyl-1,6,7,8-tetrahydro-pyrazolo
(dec); 1H NMR (300 MHz, DMSO-d6)
d
2.75e2.96 (m, 2H), 3.00e3.28
[3,4-b]quinolin-5-one (13a). Yield: 144 mg, 36%; mp: 260e262 ꢀC;
(m,1H), 3.62e3.84 (m, 2H), 6.15 (d, J¼3.0 Hz,1H), 6.30e6.39 (m,1H),
1H NMR (300 MHz, DMSO-d6)
d
1.04 (s, 6H), 2.57 (s, 2H), 3.09 (s, 2H),
7.23 (t, J¼7.0 Hz, 1H), 7.50 (t, J¼7.0 Hz, 2H), 8.23 (d, J¼7.0 Hz, 2H),
8.66 (s, 1H), 11.80 (br s, 1H); 13C NMR (100 MHz, DMSO-d6)
27.4,
6.51e6.82 (m, 2H), 6.89 (t, J¼8.0 Hz,1H), 7.10e7.31 (m, 2H), 7.52 (br s,
1H), 8.56 (s,1H), 9.38 (br s,1H); 13C NMR (100 MHz, DMSO-d6)
d
26.0,
d
31.6, 62.5, 102.5, 106.1, 110.9, 113.5, 114.0, 115.6, 121.7, 129.6, 142.6,
144.5, 146.1, 155.5, 159.3, 164.9, 192.8; HRMS (ESI) calculated for
32.2, 46.2, 51.1, 106.8, 119.2, 121.0, 124.5, 128.7, 129.5, 138.7, 150.0,
155.4, 163.0, 195.9; HRMS (ESI) calculated for C18H18N3O2 (MþHþ)
308.1399; found, 308.1387; IR (KBr), cmꢁ1: 1590, 1658, 3089.
C20H15N3O3Na (MþNaþ) 368.1011; found, 368.1051; IR (KBr), cmꢁ1
:
1537, 1600, 1667, 2232, 29,653,052, 3122, 3265.
5.5.2. 3-Hydroxy-7,7-dimethyl-1-m-tolyl-1,6,7,8-tetrahydro-pyrazolo
5.4.8. 2,5-Dioxo-7-phenyl-1-phenylamino-1,2,5,6,7,8-hexahydro-
[3,4-b]quinolin-5-one (13b). Yield: 154 mg, 37%; mp: 250e253 ꢀC; 1H
NMR (300 MHz, DMSO-d6) d 1.04 (s, 6H), 2.38 (s, 3H), 2.57 (s, 2H), 3.09
quinoline-3-carbonitrile (12h). Yield:230 mg, 50%;mp:227e229ꢀC;
1HNMR(300 MHz,DMSO-d6)
d
2.64e2.76(m,1H), 2.88e3.17(m, 2H),
(s, 2H), 7.05 (d, J¼7.0 Hz,1H), 7.37 (t, J¼7.0 Hz,1H), 8.00 (s,1H), 8.06 (d,
3.34e3.71 (m, 2H), 6.71 (d, J¼8.0 Hz, 2H), 6.90 (t, J¼7.0 Hz, 1H),
J¼7.0 Hz,1H), 8.65 (s,1H),11.90 (br s,1H); 13C NMR (100 MHz, DMSO-
7.16e7.36 (m, 7H), 8.62 (s, 1H), 9.37 (s, 1H); 13C NMR (100 MHz,
d6)
d 21.1, 27.5, 32.3, 46.4, 51.2, 106.9, 116.6, 119.8, 121.1, 125.4, 128.7,
DMSO-d6)
d
26.2, 33.9, 38.2, 114.2, 115.8, 116.3, 116.6, 127.6, 127.7,
129.6, 138.2, 138.8, 150.1, 155.5, 163.1, 196.0; HRMS (ESI) calculated for
129.4, 142.7, 143.0, 144.8, 156.7, 159.1, 159.6, 165.8, 192.9; HRMS (ESI)
calculated for C22H17N3O2Na (MþNaþ) 378.1218; found, 378.1215; IR
(KBr), cmꢁ1: 1657, 1673, 2230, 3266.
C19H19N3O2Na (MþNaþ) 344.1375; found, 344.1389; IR (KBr), cmꢁ1
:
1598, 1656, 2865, 2953, 3126.
5.5.3. 1-(4-Fluoro-phenyl)-3-hydroxy-7,7-dimethyl-1,6,7,8-tetrahy-
dro-pyrazolo[3,4-b]quinolin-5-one (13c). Yield: 144 mg, 34%; mp:
262e264 ꢀC after recrystallization from ethyl acetate; 1H NMR
5.4.9. 1-(4-Fluoro-phenylamino)-2,5-dioxo-7-phenyl-1,2,5,6,7,8-hex-
ahydro-quinoline-3-carbonitrile (12i). Yield: 218 mg, 45%; mp:
127e129 ꢀC (dec); 1H NMR (300 MHz, DMSO-d6)
d
2.69 (d, 1H),
(300 MHz, DMSO-d6) d 1.06 (s, 6H), 2.60 (s, 2H), 3.12 (s, 2H), 3.09 (s,
2.90e3.11 (m, 2H), 3.49e3.65 (m, 2H), 6.70e6.80 (m, 2H), 7.21e7.38
2H), 7.33e7.43 (m, 2H), 8.22e8.29 (m, 2H), 8.69 (s, 1H), 12.10 (br s,
1H); HRMS (ESI) calculated for C18H16N3O2Na (MþNaþ) 348.1124;
found, 348.1157; IR (KBr), cmꢁ1: 1658, 1738, 2969, 3026, 3091.
(m, 5H), 8.61 (s, 1H), 9.34 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d
33.9, 38.0, 114.2, 115.3, 115.8, 116.3, 116.6, 127.6, 127.7, 129.4, 142.7,
143.0, 144.9, 156.7, 159.1, 159.6, 165.8; HRMS (ESI) calculated for
C22H16N3O2NaF (MþNaþ) 396.1124; found, 396.1139; IR (KBr),
cmꢁ1: 1505, 1671, 2231, 3031, 3260.
5.5.4. 7-Furan-2-yl-3-hydroxy-1-phenyl-1,6,7,8-tetrahydro-pyrazolo
[3,4-b]quinolin-5-one (13d). Yield: 49 mg, 11%; mp: 230e232 ꢀC; 1H
NMR (300 MHz, DMSO-d6) d 2.78e3.06 (m, 2H), 3.40e3.65 (m, 2H),
5.4.10. 7-(4-Chloro-phenyl)-2,5-dioxo-1-phenylamino-1,2,5,6,7,8-
3.65e3.83 (m, 1H), 6.16 (d, J¼3.0 Hz, 1H), 6.34 (dd, JI¼7.0 Hz,
JII¼3.0 Hz, 1H), 7.23 (t, J¼7.0 Hz, 1H), 7.42e7.60 (m, 3H), 8.22 (d,
J¼8.0 Hz, 2H), 8.67 (s, 1H), 12.00 (br s, 1H); 13C NMR (100 MHz,
hexahydro-quinoline-3-carbonitrile (12j). Yield: 273 mg, 54%; mp:
217e219 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
2.68 (d, 1H), 2.89e3.20
(m, 2H), 3.51e3.69 (m, 2H), 6.68e6.80 (m, 2H), 7.21e7.38 (m, 5H),
8.61 (s, 1H), 9.34 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
33.6, 37.6,
DMSO-d6)
d 31.5, 36.8, 41.4, 104.6, 106.8, 109.7, 118.9, 121.2, 124.2,
d
128.4,129.4,138.3,141.3, 149.3,155.2, 155.4,162.0,194.2; HRMS (ESI)
calculated for C20H15N3O2Na (MþNaþ) 368.1011; found, 368.1049; IR
(KBr), cmꢁ1: 1593, 1656, 3132.
113.7,114.1, 115.8,121.9,129.3,129.6,129.9,132.3,142.0,144.8,146.3,
159.6, 165.7, 192.6; HRMS (ESI) calculated for C22H16N3O2NaCl
(MþNaþ) 412.0829; found, 412.0855; IR (KBr), cmꢁ1: 1649, 1673,
2229, 2874, 2952, 3052, 3267.
5.6. General procedure for the synthesis of N-substituted
2-pyridone-3-carboxylic acid amides 15
5.4.11. 7-(4-Chloro-phenyl)-1-(4-fluoro-phenylamino)-2,5-dioxo-
1,2,5,6,7,8-hexahydro-quinoline-3-carbonitrile (12k). Yield: 233 mg,
The requisite aniline (7.2 mmol) was dissolved in acetic acid
(15 mL). Piperidinium 2-[2-cyano-2-(N0-phenyl-hydrazinocarbonyl)-
vinyl]-5,5-dimethyl-3-oxo-cyclohex-1-enate 9a (2.89 g, 6.6 mmol)
was added and the solution stirred at room temperature for
10e15 min. Followingthis, water(15 mL)was addedtoprecipitatethe
product. The solid product was filtered off, washed with water, and
dried. Generally, the product obtained in this manner did not require
additional purification.
44%; mp: 165e167 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 2.68 (d, 1H),
2.89e3.21 (m, 2H), 3.50e3.68 (m, 2H), 6.67e6.80 (m, 2H), 6.95e7.12
(m, 2H), 7.30e7.45 (m, 4H), 8.61 (s, 1H), 9.34 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 33.8, 37.6, 114.2, 115.8, 116.3, 116.6, 129.3,
129.6, 132.3, 142.0, 142.7, 144.9, 159.6, 165.7, 193.0; HRMS (ESI) cal-
culated for C22H15N3O2NaClF (MþNaþ) 430.0735; found, 430.0754;
IR (KBr), cmꢁ1: 1647, 16,734, 2231, 2891, 2952, 3052, 3274.
5.5. General procedure for the synthesis of
pyrazoloquinolinones 13
5.6.1. 1-(4-Fluoro-phenyl)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahy-
dro-quinoline-3-carboxylic acid N0-phenyl-hydrazide (15a). Yield:
1.77 g, 64%; mp 191e195 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 0.97 (s,
The corresponding methylenactive 1,3-dicarbonyl compound 7
(1.4 mmol) was mixed with DMF-DMA (167 mg, 1.4 mmol) and
stirred for 5 min at room temperature. The resulting enamine 11 was
diluted with 2-propanol (1 mL). To the solution of enamine 11 in
2-propanol was added the requisite hydrazide 8 (1.3 mmol) and
6H), 2.44 (s, 4H), 6.71e6.76 (m, 3H), 7.15 (t, J¼8.1 Hz, 2H), 7.49 (t,
J¼8.8 Hz, 2H), 7.51e7.55 (m, 2H), 8.08 (d, J¼3.6 Hz, 1H), 8.78 (s, 1H),
10.45 (d, J¼3.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d 28.4, 33.2,
42.6, 50.0, 112.9, 114.0, 117.5, 119.1, 119.5, 129.5, 130.9, 134.0, 140.1,
149.5, 160.6, 161.6, 163.2, 163.5, 194.2; HRMS (ESI) calculated for

2940
S.A. Yermolayev et al. / Tetrahedron 67 (2011) 2934e2941
C25H26N3O4Na (MþNaþ) 432.1923; found, 432.1930; IR (KBr), cmꢁ1
:
234 mg, 37%; mp 218e220 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 1.00
(s, 6H), 2.15 (s, 3H), 2.28 (s, 3H), 2.46 (s, 2H), 2.80 (br s, 1H), 3.15 (br
s, 1H), 6.01 (d, J¼8 Hz, 1H), 6.76 (d, J¼8 Hz, 1H), 6.95 (s, 1H), 7.70 (s,
1H), 8.39 (s, 1H), 8.40 (s, 1H), 8.78 (s, 1H); 13C NMR (100 MHz,
1657, 1710, 2959, 3301.
5.6.2. 1-(3-Chloro-phenyl)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hex-
ahydro-quinoline-3-carboxylic acid N0-phenyl-hydrazide (15b).
Yield: 1.72 g, 60%; mp 212e214 ꢀC; 1H NMR (300 MHz, DMSO-d6)
DMSO-d6) d 28.4, 28.6, 29.3, 30.1, 34.4, 43.3,109.6,113.0,119.1,122.3,
122.9, 137.5, 144.7, 148.9, 161.0, 163.7, 164.9, 167.0, 194.0; IR (KBr),
cmꢁ1: 1509, 1544, 1695, 2953, 3148, 3350; MS (EI) m/z: 353(Mþ),
354, 336, 321, 218. Anal. Calcd (C20H23N3O3): C, 67.97; H, 6.56; N,
11.89. Found: C, 68.19; H, 6.62; N, 11.87.
d
0.99 (s, 6H), 2.44 (s, 4H), 6.72e6.75 (m, 3H), 7.16 (t, J¼7.8 Hz, 2H),
7.48 (s, 1H), 7.65e7.72 (m, 3H), 8.08 (d, J¼3.7 Hz, 1H), 8.78 (s, 1H),
10.41 (d, J¼3.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d 28.4, 33.3,
42.5, 50.1, 113.0, 114.1, 119.2, 119.5, 127.6, 128.8, 129.8, 130.4, 132.2,
134.7, 139.0, 140.2, 149.5, 160.2, 163.0, 163.4, 194.2. Anal. Calcd
(C24H22ClN3O3): C, 66.13; H, 5.09; N, 9.64. Found: C, 66.02; H, 5.00; N,
9.69; IR (KBr), cmꢁ1: 1637, 1677, 2918, 3437.
5.8. X-ray study for the compounds 13a and 18c
The compound 18c exists in the crystal phase as the hemisolvate
with acetone (Fig. 2). The cyclohexenone ring in the molecules 13a
and 18c adopts a sofa conformation where the deviation of the C3
5.6.3. 1-(2-Methoxy-phenyl)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hex-
ahydro-quinoline-3-carboxylic acid N0-phenyl-hydrazide (15c).
Yield: 1.79 g, 63%; mp 165e167 ꢀC; 1H NMR (300 MHz, DMSO-d6)
ꢀ
atom from plane of remaining atoms of ring is 0.68 A in molecule
ꢀ
13a and ꢁ0.64 A in molecule 18c (Figs. 1 and 2). The phenyl sub-
d
0.97 (d, J¼23.6 Hz, 6H), 2.21 (d, J¼17.8 Hz, 1H), 2.47 (d, J¼6.2 Hz,
stituent in the molecule 13a is almost coplanar to the plane of
pyrazole heterocycle (the C10eN3eC13eC18 torsion angle is ꢁ12.1
(2)ꢀ) due to the formation of the C14eH/N2 and C18eH/N1ꢀweak
2H), 2.60 (d, J¼17.8 Hz, 1H), 3.82 (s, 3H), 6.70e6.76 (m, 3H),
7.13e7.21 (m, 3H), 7.32 (d, J¼7.9 Hz, 1H), 7.40 (d, J¼7.9 Hz, 1H),
7.59 (t, J¼7.9 Hz, 1H), 8.05 (d, J¼3.6 Hz, 1H), 8.78 (s, 1H), 10.43 (d,
J¼3.6 Hz, 1H); HRMS (ESI) calculated for C24H23N3O3Na (MþNaþ)
420.1723; found, 420.1627; IR (KBr), cmꢁ1: 1601, 1672, 2957,
3281.
ꢀ
intramolecular hydrogen bonds (H/N 2.40 A, CeH/N 101 and
ꢀ
ꢀ
H/N 2.41 A, CeH/N 126 , respectively). The carbamide group in
the molecule 18c is coplanar to the pyridine ring (the
C7eC8eC10eO2 torsion angle is 1.6 (3)ꢀ). Such conformation of
this substituent is stabilized by the N3eH/O1 intramolecular hy-
5.7. General procedure for the synthesis of 2-pyridone-3-
carboxylic acid amides 18
ꢀ
ꢀ
drogen bond (H/O 2.05 A, NeH/O 128 ). Dimethylphenyl group
of the substituent at the N1 atom is orthogonal to the pyridine ring
and is slightly turned relatively the hydrazine fragment (the
C1eN1eN2eC11 and N1eN2eC11eC16 torsion angles are 103.1
(2)ꢀ and ꢁ21.8 (3)ꢀ, respectively). The N2 atom of the hydrazine
fragment has pyramidal configuration where the sum of bond an-
gles centered on this atom is 348ꢀ.
Dimethylammonium
2-(2-carbamoyl-2-cyano-1-ethenyl)-
5,5-dimethyl-3-oxo-1-cyclohexen-1-olate 4a14 (500 mg, 1.8 mmol)
was dissolved in water (10 mL). The requisite arylhydrazine hy-
drochloride (1.8 mmol) was dissolved in water (10 mL) at 40 ꢀC. The
two solutions were combined and stirred vigorously. The oily res-
idue came out of the aqueous reaction mixture and crystallized
during stirring for 1 h. The resulting reddish precipitate was filtered
out, washed by 2 mL of 2-propanol and dried under vacuum.
Alternatively, 2-pyridone-3-carboxylic acid amide 18c can be
obtained via hydration of 2-pyridone-3-carbonitrile 9c (307 mg,
1.0 mmol) by heating at reflux temperature in dioxane (3 mL) with
an excess of acetamide (590 mg, 10.0 mmol), PdCl2 (17.6 mg,
10 mol %), and durene (40 mg, 30 mol %). A 30% conversion was
observed by HPLC and 1H NMR.
In the crystal phase the molecules 13a and 18c has similar main
packing motif forming the centrosymmetric dimers due to the forꢀ-
00
ꢀ
mation of the O2eH/O1 (2ꢁx,1ꢁy,1ꢁz) H/O 1.74 A OeH/Oꢀ176
and C7eH/O100 (2ꢁx, 1ꢁy, 1ꢁz) H/O 2.31 A CeH/O 142 in-
ꢀ
termolecular hydrogen bonds in the case oꢀf 13a and the N3eH/O200
ꢀ
(2ꢁx, 3ꢁy, 1ꢁz) H/O 1.98 A NeH/O 170 in the case of 18c.
Atomic coordinates and crystallographic parameters have been
deposited to the Cambridge Crystallographic Data Centre (CCDC
799081 for 13a and 799080 for 18c).
Acknowledgements
5.7.1. 7,7-Dimethyl-2,5-dioxo-1-phenylamino-1,2,5,6,7,8-hexahydro-
quinoline-3-carboxylic acid amide (18a). Yield: 240 mg, 41%; mp
The Fulbright Foundation is thanked for giving an opportunity
to perform current research study and The National Science
Foundation (NEL) for funding (CAREER award CHE-0847262).
230e232 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 1.04 (s, 6H), 2.49 (s,
2H), 2.80 (d, J¼15 Hz, 1H), 3.23 (d, J¼15 Hz, 1H), 6.66 (d, 2H), 6.89 (t,
1H), 7.24 (t, 2H), 7.74 (s,1H), 8.39 (s,1H), 8.80(s,1H), 9.29 (s,1H); 13C
NMR (100 MHz, DMSO-d6) d 28.4, 28.6, 32.8, 44.9,113.2, 113.4,119.7,
Supplementary data
121.6, 120.9, 130.0, 139.9, 146.9, 158.9, 162.2, 163.1, 164.2, 194.2;
HRMS (ESI) calculated for C18H19N3O2Na (MþNaþ) 348.1324; found,
348.1354; IR (KBr), cmꢁ1: 1672, 2887, 2959, 3280, 3389.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.052.
5.7.2. 7,7-Dimethyl-2,5-dioxo-1-m-tolylamino-1,2,5,6,7,8-hexahy-
dro-quinoline-3-carboxylic acid amide (18b). Yield: 214 mg, 35%;
References and notes
mp 212e214 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 1.01 (s, 6H), 2.20 (s,
1. Ciufolini, M. A.; Chan, B. K. Heterocycles 2007, 74, 101.
2. Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
3. Medina-Franco, J. L.; Martínez-Mayorga, K.; Juarez-Gordiano, C.; Castillo, R.
3H), 2.47 (s, 2H), 2.75 (d, J¼19 Hz, 1H), 3.20 (d, J¼19 Hz, 1H),
6.37e6.50 (m, 2H), 6.89 (d, 1H), 7.08 (d,1H), 7.73 (s, 1H), 8.38 (s, 1H),
ꢁ
8.77(s, 1H), 9.20 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 28.5, 28.6,
ChemMedChem 2007, 2, 1141.
4. Gadekar, S. M. DE Patent 2555411, 1976; Chem. Abstr. 1976, 85, 198163b.
5. Otsubo, K.; Morita, S.; Uchida, M.; Yamasaki, K.; Kanbe, T.; Shimizu, T. Chem.
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6. Gupta, A. K.; Kohli, Y. Br. J. Dermatol. 2003, 149, 296.
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Cardiol. 1996, 28, 2491.
30.1, 33.2, 43.8, 110.2, 113.0, 118.0, 120.6, 122.9, 135.3, 141.9, 147.9,
160.0, 163.2, 165.0, 166.2, 193.0; HRMS (ESI) calculated for
C19H21N3O2Na (MþNaþ) 362.1114; found, 362.1124; IR (KBr), cmꢁ1
:
1680, 1695, 2880, 2959, 3045, 3246, 3370.
8. (a) Seidel, A.; Brunner, S.; Seidel, P.; Fritz, G.; Herbarth, O. Br. J. Cancer 2006, 94,
1726; (b) Yang, Z.; Hutter, D.; Sheng, P.; Sismour, M. A.; Benner, S. A. Nucleic
Acids Res. 2006, 34, 6095; (c) Sollogoub, M.; Fox, K. R.; Powersa, V. E. C.; Browna,
5.7.3. 1-(2,4-Dimethyl-phenylamino)-7,7-dimethyl-2,5-dioxo-
1,2,5,6,7,8-hexahydro-quinoline-3-carboxylic acid amide (18c). Yield:

S.A. Yermolayev et al. / Tetrahedron 67 (2011) 2934e2941
2941
T. Tetrahedron Lett. 2002, 43, 3121; (d) Sun, Z.; Ahmed, S.; McLaughlin, L. W. J.
Org. Chem. 2006, 71, 2922.
9. Bondavalli, F.; Bruno, O.; Presti, E. L.; Menozzi, G.; Mosti, L. Synthesis 1999, 1169.
10. Fossa, P.; Menozzi, G.; Dogiro, P.; Floreani, M.; Mosti, L. Bioorg. Med. Chem. 2003,
11, 4749.
11. Trummer, I.; Zeigler, E.; Wolfbeis, O. S. Synthesis 1981, 225.
12. Bellassoued-Fargeau, M.-C.; Graffe, B.; Sacquet, M.-C.; Maitte, P. J. Heterocycl.
Chem. 1985, 22, 713.
13. Gorobets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron 2004, 60, 8633.
14. Yermolayev, S. A.; Gorobets, N. Y.; Lukinova, E. V.; Shishkin, O. V.; Shishkina, S. V.;
Desenko, S. M. Tetrahedron 2008, 64, 4649.
18. For the preparation of cyclohexandiones 10bed, see: Khachatryan, D. S.;
Morlyan, N. M.; Mirzoyan, R. G.; Badanyan, S. O. Arm. Khim. Zh. 1981, 34, 665.
19. For the preparation of N-BOC-piperidinedion see: Vanotti, E.; Amici, R.;
Bargiotti, A.; Berthelsen, J.; Bosotti, R.; Ciavolella, A.; Cirla, A.; Cristiani, C.;
D’Alessio, R.; Forte, B.; Isacchi, A.; Martina, K.; Menichincheri, M.; Molinari, A.;
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21. Arnett, E. M.; Harrelson, J. A., Jr. J. Am. Chem. Soc. 1987, 109, 809.
22. Pyridone 16 was obtained in low yield (<10%) by reflux of enolate 9a for
10 min in i-PrOH with 2.0 equiv of acetic acid. Amounts of this compound
15. Yermolayev, S. A.; Gorobets, N. Y.; Desenko, S. M. J. Comb. Chem. 2009, 11, 44.
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senko, S. M. Izv. Akad. Nauk, Ser. Khim. 2008, 2, 412 (English translation Russ.
Chem. Bull. 2008, 57, p 422).
was only enough to characterize it by 1H NMR (300 MHz, DMSO-d6):
d 1.03
(s, 6H), 2.41 (s, 2H), 2.82 (s, 2H), 6.64e6.78 (m, 3H), 7.13 (t, J¼7.8 Hz, 2H),
8.00 (d, J¼2.6 Hz, 1H), 8.60 (s, 1H), 10.62 (d, J¼2.6 Hz, 1H) and MS (EI) m/z:
325(Mþ).
17. Weissberger, A.; Porter, H. D. J. Am. Chem. Soc. 1943, 65, 52 A representative 5a
was described earlier.
23. Boyer, R. D., Jr.; Denman, S. L.; Cesa, M. C.; Pagnotta, M. US Patent Appl.
5449808, 1990; Chem. Abstr. 1990, 113, 151857.