Synthesis of pyridin-2(1 H)-one derivatives via enamine cyclization

Article abstract of DOI:10.1021/jo200197g

The nucleophilic vinylic substitution reaction of the aliphatic enaminone 3-dimethylamino-2-formyl acrylonitrile 1 with the nucleophiles malononitrile and ethyl cyanoacetate produced the two unusual reaction adducts 3a and 3b in good to moderate yield und

Full text of DOI:10.1021/jo200197g

ARTICLE
pubs.acs.org/joc
Synthesis of Pyridin-2(1H)-one Derivatives via Enamine Cyclization
Sandip Chikhalikar,† Vijay Bhawe,*,† Bhausaheb Ghotekar,‡ Madhukar Jachak,‡ and Maruti Ghagare*,‡
†Department of Chemistry, Bharatiya Vidya Bhavan’s N.M. Institute of Science, Bhavan’s College, Munshi Nagar, Andheri (W),
Mumbai 400058, M.S. India
‡Department of Chemistry, Organic Chemistry Research Centre, K.T.H.M. College, Gangapur Road, Nasik 422002, M.S. India
S Supporting Information
b
ABSTRACT: The nucleophilic vinylic substitution reaction of
the aliphatic enaminone 3-dimethylamino-2-formyl acryloni-
trile 1 with the nucleophiles malononitrile and ethyl cyanoace-
tate produced the two unusual reaction adducts 3a and 3b in
good to moderate yield under milder reaction conditions. Upon
reaction with aromatic amines, these adducts yielded enamines
4 and 5, which eventually cyclized in the presence of base to
produce the novel pyridin-2(1H)-one derivatives 8 and 9.
’ INTRODUCTION
The chemistry of enamines and enaminones has numerous
attractive features that have made them important building
blocks in current organic trends.1 They have gained considerable
prominence due to their use in the treatment of epilepsy and
because they possess a variety of other medicinal properties.2
Over the decades, enaminones have been used for the synthesis
of a wide variety of heterocyclic compounds.3
Likewise, the pharmacological importance of pyridin-2(1H)-
one and its prevalent use as a synthetic intermediate in a number
of heterocyclic compounds have emerged as important topics for
researchers in recent years. These heterocyclic compounds are
also known to possess antitumor activity and decrease the
toxicity of cancer chemotherapy.4
Their evolution as valuable reagents with promising applica-
tions in heterocyclic chemistry,4 along with the development of
useful method for the synthesis of pyridin-2(1H)-ones via
enamine cyclization, is the subject of this study.
Figure 1. Synthesis and utility of enaminone 1.
’ RESULTS AND DISCUSSION
To address this point, in this paper we report the synthesis of
stable reaction adducts (3a and 3b) generated following unusual
Preparation of Enaminone 1. 3-Dimethylamino-2-formyl
reactivity of enaminone 1 toward nucleophilic reagents. The
acrylonitrile 1 was first prepared by Trofimenko from 3-amino-
nucleophilic reagents selected were malononitrile and ethyl
cyanoacetate, and the reaction was carried out at ambient
2-cyanoacrolein and dimethyl amine, whereas Reichardt and
Kermer demonstrated the synthesis of enaminone 1 via Vilsmeierꢀ
temperature in the presence of an inorganic base.
Haack formylation of acetonitrile. In 1993 we reported a new
The structure of 1 is composed of an R,β-unsaturated enone
route toward the synthesis of 1 wherein cyanoacetaldehyde was
moiety and an enamine subunit. Hence this molecule can behave
treated with dimethylformamide-dimethylacetal to offer 1 in good
both as an electrophile and as a nucleophile. This property of the
to moderate yield (Figure 1).5
molecule prompted us to carry out investigations concerning its
The synthetic utility of this enaminone has been reported by
reaction with nucleophilic reagents. Of the nucleophilic reagents
us6 and other researchers7 in the recent past. Though there have
been a number of articles showcasing the reactivity of 1, very little
work has been reported about its behavior toward nucleophilic
Received: January 27, 2011
Published: April 12, 2011
reagents.8
r
2011 American Chemical Society
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Scheme 1. Regeoselectivity of Enaminone 1 with
Nucleophiles
Table 1. (SNV) Reaction Adducts 3a and 3b
a,b Reaction conditions: Nucleophilic reagents (a2.0 mmol; b2.5 mmol),
K2CO3 (a2.5 mmol; b3.0 mmol). The reaction was carried out in
acetonitrile (ACN, 5.0 mL) under a nitrogen atmosphere at ambient
temperature. c Isolated yields were obtained.
Figure 2. Mechanism of SNV reaction of enaminone 1.
unsaturated carbon atom to which the dimethyl amine part is
attached, C1 and C3, respectively. Hence there is competition
between the C1 and C3 atoms in reacting with nucleophilic
organic substrates. Over the decades, researchers have found that
the C1 carbon atom of the aliphatic enaminones preferentially
reacts with nucleophilic reagents under multiple sets of
conditions.9,10 Nonetheless, there have been a few reports
demonstrating the participation of the C3 carbon atom rather
than the C1 carbon atom.11 Unfortunately most of the cited
studies indicate the unstable nature of the reaction products
obtained, which either reacted instantaneously with other or-
ganic substrates or underwent self-rearrangement, allowing no
control over the final reaction product.
available, compounds with active methylene groups that can act
as nucleophiles were selected. We screened the reactions of 1
with alkyl acetoacetate esters, open and cyclic ketones containing
active methylene sites and malononitrile, as reported in the
literature.9 However 1 failed to undergo any reactions under
various reaction conditions.
Though the results were discouraging, to our surprise 1
showed unusual reactivity with ethyl cyanoacetate and malono-
nitrile in the presence of an inorganic base such as potassium
carbonate. The reaction was found to be regioselective at the C3
carbon atom of 1 and followed the nucleophilic vinylic substitu-
tion pathway (SNV) instead of a Knovenagel condensation
reaction at the C1 carbonyl carbon atom (Scheme 1, Figure 2).
It is noteworthy that both the above nucleophiles failed to react
with 1 during our initial screenings with active methylene groups
as reported in the literature.9,10
In contrast to the above observations, we successfully isolated
the SNV reaction adducts 3a and 3b with efficient product yields
of 80ꢀ90% (Table 1).
The configurations of 3a and 3b around the trisubstituted
double bond were determined by 2D ROESY experiments and were
found to be retaining the configuration of 1, i.e. (E)-configuration,
The structure of enaminone 1 has two electron-deficient sites,
one being the carbonyl carbon atom and the other being the
Scheme 2. Enamine Synthesis from Synthones 3a and 3b
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Table 2. Preparation of Enamines 4 and 5a
a Reaction conditions: aryl amines (2 mmol). The reaction was carried out in glacial acetic acid (ACOH, 5.0 mL) under a nitrogen atmosphere at ambient
temperature. b Isolated yields were obtained.
which has been determined by NMR using steady state differ-
ential NOE.6
The role of solvent did not play a significant part in determining the
reaction kinetics, although best results were obtained when polar
aprotic solvents were used. Conversely, the substrates used as the base
were found to alter the reaction equilibrium. When we screened the
above reaction using organic bases such as triethyl amine, N-ethyl
diisopropylamine, piperidine, pyridine, etc. at varying temperatures,
no conversion was observed either in protic or aprotic solvents.
Reactions in the presence of metal alkoxide bases degraded the
enaminone 1leading to the formation of multiple unknown products.
The use of inorganic bases such as metal carbonates in a polar
aprotic solvent gave us best results when carried out at ambient
One of the important factors toward formation of 3 was the
use of a weak base to which the products remained unreactive. In
addition, the reaction proceeded at room temperature, permit-
ting the use of milder reaction conditions. Both of the nucleo-
philic reagents were reacted with 1 in the presence of potassium
carbonate at ambient temperature. The solvent of choice for the
reaction was acetonitrile, and we selected inorganic bases over
organic bases as in the presence of the latter the SNV reaction did
not occur.
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Scheme 3. Proposed Synthetic Pathway towards Synthesis of Pyridin-2(1H)-one Derivatives
temperature. Additionally, the use of ammonia in combination
with metal carbonates accelerated the reaction rate. The reason
could be the replacement of the dimethylamine group with an
NH2 group prior to nucleophilic attack and NH2 being a fast
leaving group as compared to the dimethylamine group, resulting
in a faster reaction rate.
Scheme 4. Synthesis of Pyridin-2(1H)-one Derivatives
9aꢀea
Though the findings signify participation of active methylene
sites bearing an adjacent cyano group, cyanoacetic acid and
cyanoacetamide failed to react under the given reaction condi-
tions and further invention on them is in progress.
With the above discovery we obtained two novel stable
synthones, SNV reaction adducts 3a and 3b, that we could utilize
in the synthesis of higher derivatives of heterocyclic compounds.
Amid the number of heterocycles, we focused on pyridin-2(1H)-
one due to its frequent use in pharmacology4 and because there is
an urge of simple and efficient synthetic protocol for the synthesis
of functionalized N-substituted pyridin-2(1H)-onecompounds.12
Our initial approach toward the synthesis of pyridin-2(1H)-
one compounds was to develop a reliable synthetic method to
introduce aromatic amines into synthones 3a and 3b. The protic
solvent acetic acid provided the required protic condition for the
reaction to occur and permitted product precipitation. Initially,
the substituted anilines formed imines with the carbonyl moiety
of 3a and 3b under protic conditions at ambient temperature,
which upon further rearrangement yielded substituted aromatic
enamines 4 and 5 (Scheme 2, Table 2).
The stereochemistry of 5 was determined by NMR using 2D
ROESY experiments. The presence of crosspeaks between Ha,
NH, and ArH hydrogens along with Ha and Hb hydrogens
indicated existence of equilibrium between (E)- and (Z)-isomers
at trisubstituted double bond (2), whereas the presence of
crosspeaks between Ha and ester hydrogens for enamine 5
indicated (E)-configuration at trisubstituted double bond (20).
Our next goal was to achieve the nucleophilic addition of the
enamine NH group to the cyano group of 4 and 5 (Scheme 3).
The paucity of reports in the literature suggests that enamines
have little tendency to undergo this type of transformation.13
Consistent with this, we also experienced difficulty in carrying
out analogous nucleophilic attacks. All the initial reactions with
organic bases and metal carbonates failed to produce any
significant results. In contrast, we found that the presence of
metal hydroxide played a vital role in promoting the reaction.
The enamines 4aꢀe and 5aꢀe were cyclized in the presence of
sodium hydroxide at ambient temperature in polar protic sol-
vents such as methanol. The molecular identification of enamines
4 resulting from malononitrile-substituted synthone 3a was
consistent with our initial hypothesis (Scheme 3).
a Note: Actual path followed by enamines 5 toward formation of pyridin-
2(1H)-one derivatives 9.
(Scheme 4, Table 3). In both cases, isolation of intermediates
6, 7a, and 7b were unsuccessful as they rapidly hydrolyzed to give
8 and 9, respectively, due to presence of alkali base within the
reaction mass. Presumably the addition of water after reaction
completion further eased the hydrolysis.
’ CONCLUSIONS
Moderate to excellent yields were obtained for most of the
derivatives reported in this paper, and an operationally simple,
inexpensive, and efficient method to prepare 1,3,5-substituted
pyridin-2(1H)-one derivatives 8aꢀe and 9aꢀe starting from
enaminone 1 has been developed.
To the best of our knowledge, this is the first report of the
synthesis of substituted pyridin-2(1H)-one derivatives using
enamine as a preparatory material using the proposed synthetic
pathway described above. It may be possible to develop relevant
potent molecules by elaborating on this synthetic approach.
Furthermore, the fact that the aliphatic enaminone underwent
unusual SNV type reactions with nucleophiles as reported here
has identified two stable novel synthones (3a and 3b), which
opens the possibility of synthesizing more diverse heterocycles.
’ EXPERIMENTAL SECTION
The enamines 5 obtained from the cyanoacetate-substituted
synthone 3b first underwent ester hydrolysis to produce acid 7a
and then underwent the nucleophilic addition reaction to
produce 1,3,5-substituted pyridin-2(1H)-one derivatives 9
General. Unless otherwise stated, materials were obtained from
commercial suppliers and were used without further purification. Start-
ing material 3-dimethylamino-2-formyl acrylonitrile was prepared as per
our previously reported procedure.5 All the reactions were carried out
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Table 3. Preparation of Pyridin-2(1H)-one Derivatives 8 and 9a
The solvent for NMR spectra was DMSO-d6 unless otherwise stated.
The 2D ROESY NMR experiments were carried out with 400 data points
along the F1 dimension and 2 K data points along the F2 dimensions. An
appropriate spinlock field was applied for a period of 300 ms. Infrared
spectra were taken in potassium bromide pallets.
Mass spectrum was recorded with an ionization potential of 70 eV.
Elemental analysis was within (0.4 of the theoretical percentage.
Preparative procedures for all the intermediates and final compounds
are provided below. The obtained products were moisture- and oxygen-
stable at ambient temperature.
2,4-Dicyano-5-oxo-pent-3-enenitrile (3a). In to an oven-dried
flask were added 3-dimethylamino-2-formyl acrylonitrile 1 (0.124 g, 1.0
mmol), malononitrile (0.132 g, 2.0 mmol) and acetonitrile (5 mL)
under the protection of N2 at ambient temperature. Previously oven-
dried potassium carbonate (0.345 g, 2.5 mmol) was added, and the
reaction mass was then allowed to react for further 30 min. The reaction
progress was monitored by thin layer chromatography using dichloro-
methane/methanol (9:1) as mobile phase. After completion of the
reaction the mixture was filtered through a pad of Celite, and the filtrate
was distilled until the solvent was completely removed so as to furnish
the desired product as a yellow solid (0.123 g, 85%). The authentic
sample for 3a was prepared via short column chromatography using
silica gel (60ꢀ100 mesh) and 2% methanol in dichloromethane as
eluent. Mp: 212ꢀ215 °C. Mass: (m/z) 145, 130, 117, 103, 89, 77, 66, 44.
FT-IR (KBR): 3556, 3436, 2215, 1627, 1538, 1347, 1256, 1162, 825,
772, 605 cmꢀ1. 1H NMR (499.85 MHz, TMS, DMSO-d6): δ 8.94 (s,
1H), 7.42 (d, J = 6.8 Hz, 1H), 2.48 (d, J = 7.0 Hz, 1H). 13C NMR (125.70
MHz, DMSO-d6): δ 186.5, 156.9, 119.5, 115.8, 115.7, 90.5, 34.4. Anal.
Calcd for C7H3N3O: C, 57.94; H, 2.08; N, 28.96. Found: C, 57.71; H,
1.842; N, 29.21.
2,4-Dicyano-5-oxo-pent-3-enoic Acid Ethyl Ester (3b). Into
an oven-dried flask were added 3-dimethylamino-2-formyl acrylonitrile
1 (0.124 g, 1.0 mmol), ethylcyanoacetate (0.282 g, 2.5 mmol) and
acetonitrile (10 mL) under the protection of N2 at ambient temperature.
Previously oven-dried potassium carbonate (0.414 g, 3 mmol) was
added, and the reaction mass was then allowed to react for further 30
min. The reaction progress was monitored using thin layer chromatog-
raphy using dichloromethane/methanol (9:1) as mobile phase. After
completion of the reaction the mixture was filtered through a pad of
Celite, and the filtrate was distilled until the solvent was completely
removed so as to furnish the desired product as pale yellow solid (0.170
g, 89%). The authentic sample for 3b was prepared via short column
chromatography using silica gel (60ꢀ100 mesh) and 1.5% methanol in
dichloromethane as eluent. Mp: 122ꢀ125 °C. Mass: (m/z) 192, 169,
153, 128, 113, 98, 86, 80, 68. FT-IR (KBr): 3571, 3453, 2988, 2215,
1671, 1648, 1541, 1409, 1369, 1305, 1194, 1020, 893, 787, 614 cmꢀ1. 1H
NMR (499.85 MHz, TMS, DMSO-d6): δ 8.82 (s, 1H), 8.06 (s, 1H),
4.22 (q, J = 7.4 Hz, 2H), 4.08 (s, 1H), 1.25 (t, J = 7.4 Hz, 3H). 13C NMR
(125.70 MHz, DMSO-d6): δ 181.8, 163.5, 158.3, 152.6, 120.3, 120.1,
61.2, 30.0, 14.2. Anal. Calcd for C9H8 N2O3: C, 56.25; H, 4.20; N, 14.58.
Found: C, 56.42; H, 3.96; N, 14.25.
General Procedure for Synthesis of Enamines (4aꢀe and
5aꢀe). Flame-dried 50 mL double neck flask was charged with 3a or 3b
(1 mmol) and aryl amines (2 mmol) under the protection of N2 at
ambient temperature. The reaction mass was then charged with glacial
acetic acid (5 mL) to obtain a clear solution. The mass was then allowed
to mix using magnetic stirrer for 3ꢀ12 h. The precipitated product was
filtered and washed with small amount of glacial acetic acid. The
obtained product was then dried in vacuum oven at 50ꢀ60 °C to afford
compounds 4aꢀe or 5aꢀe as yellow solids. The authentic samples were
prepared via short column chromatography using silica gel (60ꢀ100
mesh) and 1% methanol in dichloromethane as eluent.
a Reaction conditions: The reaction was carried out in methanol
(MeOH, 5.0 mL) in the presence of sodium hydroxide (NaOH, 2.5
mmol) at ambient temperature. b Isolated yields were obtained.
under nitrogen atmosphere in oven-dried flasks. Acetonitrile of analy-
tical grade was used. Thin layer chromatography (TLC) was carried out
using precoated 60 F254 plates with a thickness of 0.25 mm, and mode of
visualization was UV light (254 and 366 nm). Melting points were
1
determined in an open mouth capillaries and are uncorrected. H and
13C NMR spectra were recorded at room temperature unless specified
otherwise. Chemical shifts are reported in parts per million (ppm) as
well in Hz relative to tetramethylsilane, and the abbreviations used to
represent the multiplicity of the signal are s (singlet), bs (broad singlet),
d (doublet), dd (double doublet), t (triplet), q (quartet), and m (multiplate).
2,4-Dicyano-5-phenylamino-penta-2,4-dienenitrile (4a).
Yellow solid. Mp: 139ꢀ141 °C. Mass: (m/z) 219, 192, 165, 140, 115,
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104, 89, 77. FT-IR (KBr): 3770, 3049, 2231, 1693, 1646, 1533, 1304,
1153, 915, 772, 693 cmꢀ1. 1H NMR (499.85 MHz, TMS, DMSO-d6): δ
8.76 (s, 1H), 8.51 (s, 1H), 8.13 (s, 1H), 7.36 (t, J = 7.3 Hz, J = 7.3 Hz,
2H), 7.21 (d, J = 7.3 Hz, 2H), 7.15 (t, J = 7.4 Hz, J = 7.3 Hz, 1H). 1H
NMR (499.85 MHz, TMS, DMSO-d6, D2O): δ 9.05 (s, 1H), 8.59 (s,
1H), 7.39ꢀ7.12 (m, 5H). 13C NMR (125.70 MHz, DMSO-d6): δ 159.9,
154.7, 144.5, 130.1, 129.9, 129.2, 127.1, 127.1, 126.9, 116.0, 115.3, 104.0,
86.6. Anal. Calcd for C13H8N4: C, 70.90; H, 3.66; N, 25.44. Found: C,
71.23; H, 3.542; N, 25.71.
699 cmꢀ1
.
1H NMR (499.85 MHz, TMS, DMSO-d6): δ 11.30 (s,
1H), 8.84 (s, 1H), 8.09 (s, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.42 (t, J = 8.3
Hz, J = 7.3 Hz, 2H), 7.23 (t, J = 7.3 Hz, J = 7.3 Hz, 1H), 4.22 (q, J = 7.3
Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H). 1H NMR (499.85 MHz, TMS, DMSO-
d6, D2O): δ 8.72 (s, 1H), 8.08 (s, 1H), 7.47 (t, J = 6.3 Hz, 4H), 7.30 (t, J =
6.3 Hz, 1H), 4.26 (q, J = 7.3 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H); 13C NMR
(125.70 MHz, DMSO-d6): δ 164.5, 158.7, 153.5, 139.3 (ꢁ 2C), 126.9,
130.4 (ꢁ 2C), 119.3, 115.5, 114.1, 90.07, 81.6, 62.2, 14.7. Anal. Calcd for
C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C, 67.24; H, 4.72;
N, 15.47.
5-(4-Chloro-phenylamino)-2,4-dicyano-penta-2,4-diene-
nitrile (4b). Yellow solid. Mp: 125ꢀ129 °C. Mass analysis (EI): (m/z,
methanol) 254, 243, 226, 191, 172, 161, 136, 118, 109, 90, 75, 64, 44. FT-
IR (KBr): 3095, 2215, 1566, 1408, 1281, 1168, 1090, 1012, 831,
5-(4-Chloro-phenylamino)-2,4-dicyano-penta-2,4-dienoic
Acid Ethyl Ester (5b). Pale yellow solid. Mp: 137ꢀ142 °C. Mass
analysis (EI): (m/z, methanol) 301, 272, 254, 227,220, 192, 174, 165,
147, 138, 111, 75. FT-IR (KBr): 3287, 3219, 2991, 2220, 1703, 1649,
650 cmꢀ1 1H NMR (499.85 MHz, TMS, DMSO-d6): δ 10.71 (s,
.
1627, 1574, 1334, 1241, 1198, 1096, 989, 838 cmꢀ1. H NMR (500
1
1H), 8.36 (s, 1H), 7.87 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8
1
Hz, 2H). H NMR (499.85 MHz, TMS, DMSO-d6, D2O): δ 8.32 (s,
MHz, TMS, DMSO-d6): δ 11.32 (s, 1H), 8.82 (s, 1H), 8.06 (s, 1H), 7.53
(d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.9 Hz, 2H), 4.22 (q, J = 7.4 Hz, Hz, 2H),
1.25 (t, J = 7.4 Hz, 3H); 13C NMR (125.70 MHz, DMSO-d6): δ 163.5,
158.3, 152.6, 138.1, 129.8, 129.4, 120.3, 114.4, 113.3, 89.9, 81.4, 61.2,
14.2. Anal. Calcd for C15H12ClN3O2: C, 59.71; H, 4.01; N, 13.93,
Found: C, 59.87; H, 4.27; N, 13.64.
1H), 7.81 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H). 13C
NMR (125.70 MHz, DMSO-d6): δ 173.0, 155.4, 149.5, 134.7, 133.2,
131.3, 131.1, 129.2, 129.2, 122.6, 122.5, 118.2, 97.5. Anal. Calcd for
C13H7ClN4: C, 61.31; H, 2.77; N, 22.00. Found: C, 61.17; H, 2.558;
N, 22.28.
2,4-Dicyano-5-(2, 3-dimethyl-phenylamino)-penta-2,4-
dienenitrile (4c). Yellow solid. Mp: 208ꢀ212 °C. Mass analysis
(EI): (m/z, methanol) 248, 234, 220, 206, 193, 179, 152, 130, 117,
103, 91, 77, 65, 44. FT-IR (KBr): 3272, 2228, 1692, 1535, 1469, 1389,
1291, 1249, 1208, 903, 810, 674, 566 cmꢀ1. 1H NMR (500 MHz, TMS,
DMSO-d6): δ 9.68 (s, 1H),8.00 (s, 1H), 7.70 (s, 1H), 7.38 (d, J = 7.4 Hz,
1H), 7.32 (t, J = 7.4 Hz, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 2.31 (s,
3H), 1.94 (s, 3H). 1H NMR (499.85 MHz, TMS, DMSO-d6, D2O): δ
8.27 (s, 1H), 7.99 (s, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, J =
2,4-Dicyano-5-(2, 3-dimethyl-phenylamino)-penta-2,4-
dienoic Acid Ethyl Ester (5c). Dark yellow solid. Mp:
123ꢀ125 °C. Mass analysis (EI): (m/z, methanol) 295, 280, 266,
252, 248, 234, 220, 206, 193, 179, 152, 130, 117, 103, 84, 77. FT-IR
(KBr): 3204, 2978, 2225, 1710, 1634, 1574, 1338, 1206, 1019, 789,
1
755 cmꢀ1. H NMR (499.85 MHz, TMS, DMSO-d6): δ 10.90 (s,
1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.155 (m, 3H), 4.19 (q, J = 7.3 Hz,
2H), 2.25 (s, 3H), 2.16 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H). 13C NMR
(125.70 MHz, DMSO-d6): δ 163.7, 162.9, 152.9, 138.4, 137.8, 130.2,
128.8, 126.2, 121.3, 114.7, 113.6, 88.2, 80.2, 61.0, 19.8, 14.2, 13.9.
Anal. Calcd for C17H17N 3O 2: C, 69.14; H, 5.80; N, 14.23. Found: C,
68.82; H, 5.95; N, 14.41.
7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 2.30 (s, 3H), 1.93 (s, 3H). 13
C
NMR (125.70 MHz, DMSO-d6): δ 172.0, 153.4, 149.6, 139.0, 138.1,
133.7, 131.4, 127.4, 125.5, 125.5, 120.1, 116.9, 86.5, 19.9, 13.6. Anal.
Calcd for C15H12N4: C, 72.56; H, 4.87; N, 22.57. Found: C, 72.91; H,
5.153; N, 22.72.
2,4-Dicyano-5-(2,4-dimethyl-phenylamino)-penta-2,4-
dienoic Acid Ethyl Ester (5d). Dark brown solid. Mp: 111ꢀ113 °C.
Mass analysis (EI): (m/z, methanol) 295, 280, 266, 252, 248, 234, 220,
206, 193, 179, 153, 130, 117, 103, 77. FT-IR (KBr): 3268, 3170, 2228,
2,4-Dicyano-5-(2,4-dimethyl-phenylamino)-penta-2,4-
dienenitrile (4d). Yellow solid. Mp: 223ꢀ227 °C. Mass analysis (EI):
(m/z, methanol) 247, 234, 220, 206, 193, 179, 152, 130, 117, 103, 91.
FT-IR (KBr): 3748, 3257, 2220, 1684, 1538, 1389, 1308, 1230, 1194,
916, 839, 772, 674, 559 cmꢀ1. 1H NMR (500 MHz, TMS, DMSO-d6): δ
9.57 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.28ꢀ7.21 (m, 3H), 2.34 (s,
3H), 2.00 (s, 3H). 1H NMR (499.85 MHz, TMS, DMSO-d6, D2O): δ
8.25 (s, 1H), 8.02 (s, 1H), 7.26ꢀ7.19 (m, 3H), 2.32 (s, 3H), 2.00
(s, 3H). 13C NMR (125.70 MHz, DMSO-d6): δ 172.0, 153.4, 149.8,
139.9, 138.3, 134.6, 132.2, 128.6, 127.8, 127.7, 121.1, 116.8, 87.2, 20.7,
16.7. Anal. Calcd for C15H12N4: C, 72.56; H, 4.87; N, 22.57. Found: C,
72.64; H, 5.138; N, 22.47.
1
1705, 1635, 1557, 1342, 1205, 1175, 1021, 759, 671 cmꢀ1. H NMR
(499.85 MHz, TMS, DMSO-d6): δ 10.19 (s, 1H), 7.82 (s, 1H), 7.53 (s,
1H), 6.90 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 4.05
(q, J = 7.4 Hz, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H).
13C NMR (125.70 MHz, DMSO-d6): δ. 163.8, 163.5, 152.4, 138.0,
136.9, 130.3, 128.6, 126.1, 120.8, 114.4, 113.8, 96.4, 80.1, 61.6, 21.7, 13.8,
15.6. Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found:
C, 69.36; H, 5.97; N, 13.95.
2,4-Dicyano-5-(2,4-dichloro-phenylamino)-penta-2,4-
dienoic Acid Ethyl Ester (5e). Bright yellow solid. Mp:
123ꢀ125 °C. Mass analysis (EI): (m/z, methanol) 336, 334, 300,
288, 272, 254, 226, 191, 172, 145, 109, 75. FT-IR (KBr): 3334, 2983,
2,4-Dicyano-5-(2,4-dichloro-phenylamino)-penta-2,4-
dienenitrile (4e). Yellow solid. Mp: 134ꢀ139 °C. Mass analysis (EI):
(m/z, methanol) 288, 271, 254, 226, 191, 172, 161, 145, 118, 109. FT-IR
(KBr): 3738, 3071, 2214, 1678, 1575, 1396, 1327, 1247, 1102,
2225, 1705, 1624, 1577, 1329, 1231, 1200, 1099, 873, 764, 649 cmꢀ1
.
1H NMR (499.85 MHz, TMS, DMSO-d6): δ 10.73 (s, 1H), 8.58 (s, 1H),
7.97 (s, 1H), 7.75 (d, J = 9.8 Hz, 1H), 7.57ꢀ7.51 (m, 2H), 4.21 (q, J = 7.3
Hz, 2H), 1.24 (t, J = 7.3 Hz, 3H). 13C NMR (125.70 MHz, DMSO-d6): δ
161.4, 155.9, 141.6, 140.1, 130.9, 129.1, 128.4, 127.8, 121.7, 120.1 (ꢁ 2C),
104.5, 91.7, 64.7, 13.9. Anal. Calcd for C15H11Cl2N3O2: C, 53.59; H, 3.30;
N, 12.50. Found: C, 53.45; H, 3.22; N, 12.62.
1
771 cmꢀ1. H NMR (500 MHz, TMS, DMSO-d6): δ 10.71 (s, 1H),
8.36 (s, 1H), 7.87 (s, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.40 (dd, J = 8.6 Hz,
J = 1.9 Hz 1H), 7.13 (d, J = 1.9 Hz, 1H). 1H NMR (499.85 MHz, TMS,
DMSO-d6, D2O): δ 8.34 (s, 1H), 7.84 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H),
7.37 (t, J = 8.6 Hz, J = 2.0 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H). 13C NMR
(125.70 MHz, DMSO-d6): δ 172.7, 159.3, 155.3, 149.5, 148.9, 131.3,
131.0, 129.1, 128.9, 122.6, 122.5, 118.2, 91.5. Anal. Calcd for
C13H6Cl2N4: C, 54.01; H, 2.09; N, 19.38. Found: C, 53.70; H, 1.916;
N, 19.76.
2,4-Dicyano-5-phenylamino-penta-2,4-dienoic Acid Ethyl
Ester (5a). Pale yellow solid. Mp: 148ꢀ150 °C. Mass analysis: (m/z)
266, 238, 220, 193, 165, 140, 114, 104, 77, 64, 51. FT-IR (KBr): 3211,
2983, 2221, 1704, 1578, 1649, 1341, 1241, 1199, 1098, 992, 758,
General Procedure Preparation of Pyridin-2(1H)-ones
(8aꢀe and 9aꢀe). To a flame-dried 50 mL double neck flask 4aꢀe
or 5aꢀe (1 mmol) charged with methanol (10 mL) was added sodium
hydroxide pellets (2.5 mmol) in one portion under the protection of N2
at ambient temperature. The reaction mass was then allowed to react for
10ꢀ12 h so as to obtain a clear solution, and the reaction progress was
monitored by thin layer chromatography using dichloromethane/
methanol (9:1) as mobile phase. After completion of reaction the react
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The Journal of Organic Chemistry
ARTICLE
mass was concentrated under vacuum until the solvent was completely
removed. The obtained residue was then charged with water (10 mL)
and cooled to 5 °C. Dilute HCl was added to make the pH of the
obtained mixture acidic (pH 3ꢀ4), and the product was extracted from
aqueous phase using dichloromethane. Distillation of dichloromethane
under vacuum furnished the desired product. The authentic samples
were prepared via short column chromatography using silica gel
(60ꢀ100 mesh) and 1% methanol in dichloromethane as eluent to give
8 or 9 as final products.
2-Oxo-1-phenyl-1,2-dihydro-pyridine-3,5-dicarbonitrile
(8a). White solid. Mp: 204ꢀ207 °C. Mass analysis (EI): (m/z, methanol)
221, 206, 193, 180, 154, 140, 128, 118, 106, 91, 77. FT-IR (KBr): 3052, 2215,
1692, 1650, 1596, 1266, 1153, 769, 692 cmꢀ1. 1H NMR (500 MHz, TMS,
DMSO-d6):δ8.13 (s, 1H), 7.53 (s, 1H), 7.27 (d, J= 7.3 Hz, 2H), 7.04 (t, J=
7.9 Hz, J = 7.3 Hz, 2H), 6.82 (t, J = 7.3 Hz, J = 7.3 Hz, 1H). 13C NMR
(125.70 MHz, DMSO-d6): δ 161.2, 159.0, 153.1, 149.1, 129.1 (ꢁ 2C),
123.9, 121.5 (ꢁ 2C), 120.8 (ꢁ 2C), 100.5, 86.5. Anal. Calcd for C13H7N3O:
C,70.58; H, 3.19; N, 19.00. Found: C, 70.74; H, 2.947; N, 18.67.
1-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-pyridine-3,5-di-
carbonitrile (8b). Off white Solid. Mp: 240ꢀ245 °C. Mass analysis
(EI): (m/z, methanol) 255, 227, 192, 165, 140, 111, 75. FT-IR (KBr):
3348, 2209, 1613, 1566, 1488, 1384, 1200, 1090, 821 cmꢀ1. 1H NMR
(500 MHz, TMS, DMSO-d6): δ 8.58 (s, 1H), 8.08 (s, 1H), 7.93 (d, J =
8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H). 13C NMR (125.70 MHz, DMSO-
d6): δ 159.7, 155.1, 148.3, 138.2, 129.3, 129.3, 128.7, 126.6, 122.9, 122.8,
122.0, 105.0, 79.8. Anal. Calcd for C13H6ClN3O: C, 61.07; H, 2.37; N,
16.44. Found: C, 60.78; H, 2.183; N, 16.12.
DMSO-d6): δ 168.6, 159.3, 152.9, 149.4, 143.4, 133.1, 130.4, 130.0,
129.4, 128.9, 128.8, 120.7, 87.9. Anal. Calcd for C13H8N2O3: C, 65.00;
H, 3.36; N, 11.66. Found: C, 65.18; H, 3.127; N, 11.98.
1-(4-Chloro-phenyl)-5-cyano-2-oxo-1,2-dihydro-pyri-
dine-3-carboxylic Acids (9b). Pale brown solid. Mp: 189ꢀ193 °C.
Mass analysis (EI): (m/z, methanol) 274, 257, 229, 216, 177, 149, 127,
99, 84, 49. FT-IR (KBr): 3327, 3187, 2227, 1638, 1606, 1490, 1288,
1
1189, 946, 852 cmꢀ1. H NMR (499.85 MHz, TMS, DMSO-d6): δ
12.83 (s, 1H), 9.54 (s, 1H), 8.44 (s, 1H), 7.63 (d, J = 7.3 Hz, 2H), 7.44
(d, J = 7.3 Hz, 2H). 13C NMR (125.70 MHz, DMSO-d6): δ 170.0, 158.1,
146.2, 141.1, 132.9, 131.5, 128.7 (X2C), 124.0, 122.3 (X2C), 100.9, 81.0.
Anal. Calcd for C13H8ClN2O3: C, 56.85; H, 2.57; N, 10.20. Found: C,
56.53; H, 2.44; N, 9.91.
5-Cyano-1-(2, 3-dimethyl-phenyl)-2-oxo-1,2-dihydro-pyr-
idine-3-carboxylic Acid (9c). Pale buff colored Solid. Mp:
180ꢀ183 °C. Mass analysis (EI): (m/z, methanol) 268, 252, 238, 224,
210, 196, 179, 168, 152, 133, 120, 103, 91, 77, 65, 44. FT-IR (KBr): 3340,
1
2947, 2227, 1692, 1614, 1582, 1396, 1287, 1192, 1092, 797 cmꢀ1. H
NMR (499.85 MHz, TMS, DMSO-d6): δ 13.11 (s, 1H), 9.66 (s, 1H),
8.45 (s, 1H), 7.93 (d, J = 8 Hz, 1H), 7.06 (t, J = 7.3 Hz, 8.0 Hz, 1H), 6.93
(d, J = 7.3 Hz, 1H), 2.18 (s, 3H), 2.16 (s, 3H). 13C NMR (125.70 MHz,
DMSO-d6): δ 168.4, 160.0, 150.0, 143.9, 137.6, 137.6, 128.3, 126.5,
125.9, 122.7, 119.9, 107.4, 79.9, 20.9, 12.9. Anal. Calcd for C15H12N2O3:
C, 67.16; H, 4.51; N, 10.44. Found: C, 67.42; H, 4.762; N, 10.26.
5-Cyano-1-(2,4-dimethyl-phenyl)-2-oxo-1,2-dihydro-pyr-
idine-3-carboxylic Acid (9d). Buff colored solid. Mp: 169ꢀ174 °C.
Mass analysis (EI): (m/z, methanol) 268, 252, 238, 224, 210, 196, 179,
168, 152, 133, 120, 103, 91, 77, 44. FT-IR (KBr): 3434, 2920, 2851,
1-(2, 3-Dimethyl-phenyl)-2-oxo-1,2-dihydro-pyridine-3,5-
dicarbonitrile (8c). Buff colored solid. Mp: 245ꢀ248 °C. Mass analysis
(EI): (m/z, methanol)249, 221, 210, 196, 183, 168, 151, 132, 120, 103. FT-
1
2225, 1681, 1620, 1592, 1275, 1188, 941, 877, 800 cmꢀ1. H NMR
(499.85 MHz, TMS, DMSO-d6): δ 12.83 (s, 1H), 9.54 (s, 1H), 8.39 (s,
1H), 7.74 (d, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J = 7.9 Hz, 1H), 2.23
(s, 6H) 13C NMR (125.70 MHz, DMSO-d6): δ 168.3, 156.2, 149.3,
143.5, 134.9, 134.3, 133.1, 130.9, 128.1, 126.3, 123.1, 116.9, 79.8, 20.2,
18.0. Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found:
C, 67.55; H, 4.517; N, 10.29.
5-Cyano-1-(2,4-dichloro-phenyl)-2-oxo-1,2-dihydro-pyri-
dine-3-carboxylic Acid (9e). Yellow solid. Mp: 185ꢀ189 °C. Mass
analysis (EI): (m/z, methanol) 309 (mþ2), 300, 290, 252, 244, 226, 210,
191, 172, 160, 145, 109. FT-IR (KBr): 3330, 3168, 2228, 1688, 1646,
1579, 1509, 1388, 1232, 1101, 865, 810 cmꢀ1. 1H NMR (499.85 MHz,
TMS, DMSO-d6): δ 12.93 (s, 1H), 9.54 (s, 1H), 8.44 (s, 1H), 7.86 (d, J =
7.9 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H). 13C NMR (125.70
MHz, DMSO-d6): δ 165.1, 159.1, 146.9, 172.4, 136.3, 135.1, 134.4,
132.0, 126.3, 123.9, 123.7, 117.0, 81.9. Anal. Calcd for C13H6Cl2N2O3:
C, 50.51; H, 1.96; N, 9.06. Found: C, 50.28; H, 1.739; N, 9.19.
IR(KBr): 3265, 2226, 1691,1596, 1533, 1302, 1237, 1187, 815, 766 cmꢀ1
.
1H NMR (500 MHz, TMS, DMSO-d6): δ 9.46 (s, 1H), 8.37 (s, 1H), 8.05
(d, J = 7.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, J = 7.3 Hz, 1H), 6.94 (d, J = 7.3 Hz,
1H), 2.26 (s, 3H), 2.16 (s, 3H). 13C NMR (125.70 MHz, DMSO-d6): δ
161.4, 158.4, 156.5, 146.9, 137.0, 136.7, 127.7, 125.7, 125.4, 121.2 (ꢁ 2C),
106.2, 100.8, 20.4, 13.6. Anal. Calcd for C15H11N3O: C, 72.28; H, 4.45; N,
16.86. Found: C, 72.56; H, 4.829; N, 16.55.
1-(2,4-Dimethyl-phenyl)-2-oxo-1,2-dihydro-pyridine-3,5-
dicarbonitrile (8d). Buff colored solid. Mp: 250ꢀ255 °C. Mass
analysis (EI): (m/z, methanol) 249, 221, 210, 196, 178, 151, 132, 120,
105. FT-IR (KBr): 3391, 3293, 2221, 1633, 1581, 1392, 1224, 1155, 926,
799, 751 cmꢀ1. 1H NMR (500 MHz, TMS, DMSO-d6): δ 9.44 (s, 1H),
8.36 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J = 8.3 Hz,
1H), 2.24(s, 3H), 2.23 (s, 3H). 13C NMR (125.70 MHz, DMSO-d6): δ
161.4, 156.1, 146.9, 134.8, 132.4, 130.8, 128.0, 126.8, 122.2, 119.9 (ꢁ
2C), 100.7, 82.0, 20.4, 17.9. Anal. Calcd for C15H11N3O: C, 72.28; H,
4.45; N, 16.86. Found: C, 72.47; H, 4.751; N, 16.63.
’ ASSOCIATED CONTENT
1-(2,4-Dichloro-phenyl)-2-oxo-1,2-dihydro-pyridine-3,5-
dicarbonitrile (8e). Brown solid. Mp: 266 ꢀ269 °C. Mass analysis
(EI): (m/z, methanol) 288, 263, 248, 234, 224, 210, 196, 178, 160, 145,
126, 99, 90. FT-IR (KBr): 3454, 3362, 2199, 1619, 1596, 1471, 1247,
1104, 785, 666, 589 cmꢀ1. 1H NMR (500 MHz, TMS, DMSO-d6): δ
7.81 (s, 1H), 7.40 (s, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.20 (t, J = 2.2 Hz, J =
8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H). 13C NMR (125.70 MHz, DMSO-
d6): δ 159.3, 155.3, 149.9, 147.9, 137.1, 134.4, 131.3, 131.0, 129.1, 122.6,
122.5, 100.0, 79.7. Anal. Calcd for C13H5Cl2N3O: C, 53.82; H, 1.74; N,
14.48. Found: C, 53.55; H, 1.48; N, 14.47.
S
Supporting Information. Experimental procedures and
b
full spectroscopic data for all the compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: drvijaybhawe@gmail.com; ghagaremg@gmail.com.
5-Cyano-2-oxo-1-phenyl-1,2-dihydro-pyridine-3-car-
boxylic Acid (9a). White solid. Mp: 208ꢀ212 °C. Mass analysis (EI):
(m/z, methanol) 240/239, 223, 210, 195, 166, 142, 119, 104, 77. FT-IR
(KBr): 3312, 3164, 2229, 1682, 1632, 1589, 1273, 1186, 1006, 942, 755,
694 cmꢀ1. 1H NMR (499.85 MHz, TMS, DMSO-d6): δ 12.92 (s, 1H),
9.54 (s, 1H), 8.43 (s, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.59 (t, J = 8.0 Hz, 8.0
Hz, 2H), 7.40 (t, J = 7.9 Hz, 8.0 Hz, 1H). 13C NMR (125.70 MHz,
’ ACKNOWLEDGMENT
The authors gratefully acknowledge financial support for this
project from UGC, New Delhi, India. We thank Mamta Joshi
(National Facility for High Field NMR, T.I.F.R. Mumbai) for 2D
ROESY NMR assistance. We also acknowledge support and
facilities provided by Bhavans and K.T.H.M. Colleges M.S. India.
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ARTICLE
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