One-Pot Synthesis of 3-Cyano-2-pyridones

Article abstract of DOI:10.1002/jhet.2227

A versatile synthesis of 3-cyano-2-pyridones via a one-pot, four-component condensation of ethyl cyanoacetate, ketones, aldehydes, and ammonium acetate under very mild conditions has been developed. This method provides rapid access to this type of valuab

Full text of DOI:10.1002/jhet.2227

Month 2014
One-Pot Synthesis of 3-Cyano-2-pyridones
*
Yingcai Wang, Gang Liu, Jeremy Chris P. Reyes, and Randolph Duverna
Department of Therapeutic Discovery, Amgen Inc. 1120 Veterans BLVD., South San Francisco, CA, 94080, USA
*
E-mail: yingcai02@gmail.com
Received December 31, 2013
DOI 10.1002/jhet.2227
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A versatile synthesis of 3-cyano-2-pyridones via a one-pot, four-component condensation of ethyl
cyanoacetate, ketones, aldehydes, and ammonium acetate under very mild conditions has been developed.
This method provides rapid access to this type of valuable heterocyclic compounds from readily available
materials in a single operation.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
microwave to improve the yield [9]. By using malono-
nitrile instead of ethyl cyanoacetate, a solvent-free
synthesis of 4,6-diaryl-3-cyano-2-pyridones promoted by
sodium hydroxide at 75°C was reported [44].
To expand the substrate scope and to reduce excess
reagents, we started to explore this reaction under
solvent-free conditions at RT. We now communicate a
mild, one-pot synthesis of 3-cyano-2-pyridones with a
broad range of substrates including both aliphatic and
aromatic aldehydes and ketones.
The 3-Cyano-2-pyridones are important heterocycles
found in many pharmaceuticals (Fig. 1) [1–4]. Milrinone
[1] and Olprinone [2] belong to a class of phosphodiester-
ase III inhibitors and both were approved for heart failure
therapy. Other examples in preclinical development
include A-769662 (AMPK activator for metabolic disor-
ders) [3] and JNJ-40068782 (metabotropic glutamate
receptor mGluR2 modulator for psychiatric disorders) [4].
In addition to the continuous interest of being explored as
cardiotonic agents [5–8], 3-cyano-2-pyridones were also
explored as antitumor [5,9–14], anticoagulant [15], anti-
inflammatory, and analgesic agents [16–18].
RESULTS AND DISCUSSION
Development of methods to prepare substituted 2-
pyridones has been a significant area of research in organic
synthesis, and a multitude of cyclization strategies based
on various bond forming processes have been reported
[19–40].
On the basis of literature precedence in the synthesis of
pyridones or dihydropyridines, we screened quite a few
catalysts [Yb(OTf)3, AlCl3, Ln(OTf)3, CAN, NaOBz,
NaIO4, Li2CO3] under solvent-free condition and found
none of them gave more than 10% yield. We then looked
at secondary amines due to its prevalence in iminium
catalysis [45]. At the outset, we sought to prepare 2-pyridone
(5) from an equimolar mixture of ethyl cyanoacetate (1),
benzaldehyde (2), cyclopropylmethyl ketone (3), and
ammonium acetate at ambient temperature in open air using
various amine catalysts (Table 1). While L-proline was
reported to be an efficient catalyst for a facile unsymmetric
Hantzsch reaction preparing polyhydroquinoline derivatives
[46], it was found to be ineffective for our purpose. To our
delight, pyrrolidine (4c) gave the desired 2-pyridone (5) with
44% yield (entry 3). Aziridine (4a) was found to be
ineffective (entry 1), while treatment with azetidine (4b),
piperidine (4e) [47], and morpholine (4f) [48] led to very
low yields (entry 2, 5, and 6).
The majority of the recent syntheses of 3-cyano-2-
pyridones [5–18] utilized a one-pot four-component
condensation (ethyl cyanoacetate, aromatic aldehydes,
aromatic ketones, and excess of ammonium acetate) in
refluxing ethanol or 2-butanol [41,42]. As a significant
improvement from the multiple step reactions, this method
offers easy operation and quick assembly from readily
available aldehydes and ketones. However, it requires
excess of ammonium acetate and refluxing in alcohol
solvents, and the yield is quite variable (20–80%)
depending on the substrates. Very recently, modification
of this method was reported by either changing solvent to
polyethylene glycol (yield can be improved from 5% at
room temperature (RT) to 80% at 1 10°C) [43], or using
© 2014 HeteroCorporation

Y. Wang, G. Liu, J. C. P. Reyes, and R. Duverna
Vol 000
yields (Table 2). Although this reaction can proceed under
a solvent-free condition (Table 1), it was found that addi-
tion of a minimal amount of dimethyl sulfoxide (DMSO)
can increase the solubility of the starting materials and
intermediates to improve the yield. Both electron-donating
and electron-withdrawing groups are tolerated on aromatic
aldehydes (8a, 8b, 8c). Alkyl aldehydes (second row)
delivered similar yields at a par with aromatic aldehydes
(first row). In some cases, increasing the reaction tempera-
ture improves yield by promoting a more facile oxidation
step (e.g., 8d).
Variation of the ketones revealed that aromatic ketones
with various substituents tended to give modest yields
(Table 3, 11a–11c), while modest to good yields (59–82%)
were obtained when a series of aliphatic ketones (11d–11l)
were employed. Both electron-donating and electron-with-
drawing groups are tolerated on aromatic ketones (8a,
11a–11c). Using a methyl benzyl ketone, the method
was regioselective for the less sterically hindered methyl
instead of the activated benzylic position (11d).
Entry to bicyclic 2-pyridones and 5-substituted
pyridones was realized through the use of cyclic and
symmetric ketones, respectively (Table 4). This method
tolerates different ring sizes giving 5, 6, and 7-membered
ring-fused 2-pyridones (13a–13c).
Mechanistically, this process (Scheme 1) could occur via
a Knoevenagel condensation between ethyl cyanoacetate
1 and the aldehyde 6 followed by a Michael addition of
15 (derived from 10 and 4) to deliver the δ-keto α-cyano
esters 16, which we recently prepared under similar con-
dition without NH4OAc [49]. Other supporting evidence
for this mechanism includes liquid chromatography–mass
spectrometry (MS) detection of MS corresponding to 14
being converted to 16 over time (when R1 = R2 = Ph),
and clean reaction of 1 and 6 to give 14 promoted by
pyrrolidine (when R1 = Ph).
Figure 1. Representative drugs containing 3-cyano-2-pyridones. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
This exciting result prompted us to explore the substrate
cope of the method. Indeed, the reaction tolerates a wide
range of structural changes of both aldehydes and ketones.
Both aromatic and aliphatic aldehydes (6) can participate
in the reaction to give desired products with moderate
Table 1
Screening of secondary aminesa. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
CONCLUSION
In summary, we have developed an efficient one-pot syn-
thesis of substituted 3-cyano-2-pyridones promoted by
pyrrolidine. The mild reaction conditions and rapid assembly
from simple, readily available materials make it a very practi-
cal protocol for the synthesis of these important heterocycles.
Entry
Secondary amine
Yieldb (%)
EXPERIMENTAL
1
2
3
4
5
6
Aziridine 4a
Azetidine 4b
Pyrrolydine 4e
L-proline
Piperidine
Morpholine 4f
0
13
44
0
8
8
General information. All reactions were carried out open
to air. DMSO was purchased from EMD; ethyl cyanoacetate,
ammonium acetate, and pyrrolidine were purchased from
Aldrich. Aldehydes and ketones were purchased from common
suppliers such as Aldrich, Acros, TCI, etc. Reactions were
monitored by Agilent 1200 series LC connected to an Agilent
6140 quadrupole MS analyzer. Product purification by flash
chromatography was performed using Teledyne-ISCO Redisep
aReaction condition: a mixture of 1/2/3 = 1:1:1 (1 mmol scale) was treated
with a secondary amine (4a–f, 1.5 equiv.), followed by ammonium acetate
(1.0 equiv.), solvent free.
bIsolated yields.
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Month 2014
One-Pot Synthesis of 3-Cyano-2-Pyridones
Table 2
Screening of aldehydesa,b,c. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
aReaction condition: a mixture of 1/6/7 = 1:1:1 (1 mmol scale) was treated with pyrrolidine (1.3 equiv.), followed by
ammonium acetate (1.5–1.8 equiv.).
bDMSO (0.2 mL) as solvent.
cIsolated yields.
dHeated at 80°C.
normal phase silica gel columns (24 g size) on a Teledyne-ISCO
128.2, 127.8, 116.5, 106.2, 98.5 ppm; HRMS (TOF) Calculated
for C18H13N2O [M+H]+ 273.1023, Found: 273.1028.
1
Companion. H and 13C spectra were recorded on a Bruker 500
Methyl 4-(3-cyano-2-oxo-6-phenyl-1,2-dihydropyridin-4-yl)
benzoate (8b). (45% yield). H-NMR (500 MHz; DMSO-d6):
spectrometer in DMSO-d6. Chemical shifts are reported in δ
ppm relative to the DMSO-d6 peak at 2.50 ppm (1H) or
39.51 ppm (13C). High resolution mass spectra (HRMS) were
determined on Agilent 1200 series LC connected to an Agilent
6510 Q-TOF MS analyzer.
General procedure for the synthesis of 2-pyridones. To a
solution of ethyl cyanoacetate (1.0 mmol), aldehyde (1.0 mmol)
and ketone (1.0 mmol) in 0.2 mL DMSO was added pyrrolidine
(0.1 equiv) stirred for 1 h. Ammonium acetate (1.5 to 1.8 equiv)
was then added, and the mixture was stirred vigorously for
30 min. Pyrrolidine (1.2 equiv) was then added and stirred for
12–18 h. The reaction vessel was left uncapped and open to
atmospheric air throughout the reaction sequence. The crude
mixture, without any work-up, was purified directly by medium
pressure flash chromatography using 0–5% MeOH in DCM. All
yields refer to isolated yields unless otherwise stated.
1
δ = 12.86 (br s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.90–7.94
(m, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.47–7.62 (m, 3H), 6.85 ppm
(br s, 1H), 3.90 ppm (s, 3H); 13C-NMR (125 MHz; DMSO-d6):
δ = 165.5, 161.8, 140.4, 131.1, 131.0, 129.6, 129.3, 128.8,
128.6, 127.6, 127.2, 126.9, 116.0, 109.4, 106.0, 52.2 ppm;
HRMS (TOF) Calculated for C20H15N2O3 [M+H]+ 331.1077,
Found: 331.1085.
4-(4-Methoxyphenyl)-2-oxo-6-phenyl-1,2-dihydropyridine-3-
carbonitrile (8c). (58% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 12.71 (br s, 1H), 7.88 (d, J = 6.6 Hz, 2H), 7.73 (d, J = 8.8 Hz,
2H), 7.49–7.58 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.78 ppm
(br s, 1H), 3.84 (s, 3H); 13C-NMR (125 MHz; DMSO-d6):
δ = 162.2, 161.1, 159.2, 150.9, 132.3, 131.1, 130.0, 128.9,
128.0, 127.7, 116.9, 114.2, 105.9, 97.7, 55.4 ppm; HRMS
(TOF) Calculated for C19H15N2O2 [M+H]+ 303.1128, Found:
303.1131.
Characterization data. 6-Cyclopropyl-2-oxo-4-phenyl-1,2-
dihydropyridine-3-carbonitrile (5).
(53% yield). 1H-NMR
(500 MHz; DMSO-d6): δ = 12.66 (br s, 1H), 7.57–7.62 (m, 2 H),
7.49–7.54 (m, 3 H), 6.04 (br s, 1H), 1.92–2.01 (m, 1H), 1.09–
1.16 (m, 2H), 1.03–1.09 ppm (m, 2H); 13C-NMR (125 MHz;
DMSO-d6): δ = 161.5, 159.8, 158.8, 136.3, 130.2, 128.7, 128.0,
116.8, 101.2, 96.3, 13.7, 10.7 ppm; HRMS (TOF) Calculated for
C15H13N2O [M+H]+ 237.1023, Found: 237.1028.
4-Neopentyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile
(8d).
(27% yield at RT; 51% yield at 80°C). 1H-NMR
(500 MHz; DMSO-d6): δ = 12.62 (br s, 1H), 7.76–7.81 (m, 2H),
7.50–7.59 (m, 3H), 6.62 (br s, 1H), 2.66 (s, 2H), 1.02ppm
(s, 9H); 13C-NMR (125 MHz; DMSO-d6): δ = 161.6, 161.0, 149.7,
132.3, 131.0, 128.9, 127.5, 116.6, 108.0, 102.0, 47.5, 33.3,
29.5 ppm; HRMS (TOF) Calculated for C17H19N2O [M+H]+
267.1492, Found: 267.1500.
2-Oxo-4,6-diphenyl-1,2-dihydropyridine-3-carbonitrile
1
(8a).
(63% yield). H-NMR (500MHz; DMSO-d6): δ = 12.81
(br s, 1H), 7.90 (d, J = 7.1 Hz, 2H), 7.70–7.77 (m, 2H), 7.49–7.61
(m, 6H), 6.83ppm (br s, 1H); 13C-NMR (125MHz; DMSO-d6):
δ = 162.0, 159.8, 151.5, 136.0, 132.3, 131.2, 130.4, 128.9, 128.8,
4-Cyclohexyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile
(8e). (63% yield). H-NMR (500 MHz; DMSO-d6): δ = 12.58
(br s, 1H), 7.83 (d, J = 6.8 Hz, 2H), 7.47–7.58 (m, 3H), 6.74
1
Journal of Heterocyclic Chemistry
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Y. Wang, G. Liu, J. C. P. Reyes, and R. Duverna
Vol 000
Table 3
Screening of ketones. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(brs, 1H), 2.76 (tt, J = 11.9, 2.9 Hz, 1H), 1.82 (d, J = 12.7 Hz, 2H),
1.67–1.77 (m, 3H), 1.52–1.64 (m, 2H), 1.21–1.43 ppm (m, 3H);
13C-NMR (125 MHz; DMSO-d6): δ = 168.1, 161.6, 151.4, 132.3,
132.1, 132.3, 131.0, 128.8, 127.6, 115.7, 103.3, 99.1, 43.5, 31.1,
25.8, 25.1 ppm; HRMS (TOF) Calculated for C18H19N2O [M
6-(4-Methoxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-
carbonitrile (11a). (42% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 7.84 (d, J = 8.8 Hz, 2H), 7.66–7.70 (m, 2H), 7.52–7.56
(m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 3.80 ppm (s, 3H);
13C-NMR (125 MHz; DMSO-d6): δ = 162.4, 161.9, 160.0, 151.3,
136.4, 130.6, 129.7, 129.0, 128.2, 124.3, 116.9, 114.6, 105.4,
97.5, 55.7 ppm; HRMS (TOF) Calculated for C19H15N2O2 [M+H]+
+H]+ 279.1492, Found: 279.1489.
4-Isopropyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile
1
(8f). (53% yield). H-NMR (500 MHz; DMSO-d6): δ = 12.52
303.1128, Found: 303.1137.
(br s, 1H), 7.78–7.87 (m, 2H), 7.47–7.58 (m, 3H), 6.75
(br s, 1H), 3.12 (spt, J = 6.8 Hz, 1H), 1.27 ppm (d, J = 7.1 Hz,
6H); 13C-NMR (125 MHz; DMSO-d6): δ = 169.2, 161.5, 151.4,
132.2, 131.0, 128.8, 127.6, 115.6, 102.8, 99.1, 33.2, 21.3 ppm;
HRMS (TOF) Calculated for C15H15N2O [M+H]+ 239.1179,
Found: 239.1183.
6-(4-Chlorophenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-
carbonitrile (11b). (67% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 12.85 (br s., 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.68–7.77 (m, 2H),
7.59 (d, J = 8.8 Hz, 2H), 7.56–7.58 (m, 3H), 6.89 ppm (br s, 1H);
13C-NMR (125 MHz; DMSO-d6): δ = 162.2, 159.6, 150.5, 136.0,
135.9, 131.3, 130.4, 129.6, 128.9, 128.8, 128.3, 116.4, 106.7,
Journal of Heterocyclic Chemistry
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One-Pot Synthesis of 3-Cyano-2-Pyridones
Table 4
4-Aryl-5,6-dialkyl 3-cyano-2-pyridones.a [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
aHeated at 80°C.
2.59 (q, J = 7.6 Hz, 2H), 1.20ppm (t, J = 7.6 Hz, 3H); 13C-NMR
(125 MHz; DMSO-d6): δ = 161.5, 160.3, 157.2, 135.9, 130.3,
128.8, 128.0, 116.8, 105.1, 97.5, 26.1, 12.7ppm; HRMS (TOF)
Calculated for C14H13N2O [M+H]+ 225.1023, Found: 225.1027.
6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile
(11f). (54% yield). 1H-NMR (500 MHz; DMSO-d6): δ = 12.60
(br s, 1H), 7.57–7.62 (m, 2H), 7.51–7.57 (m, 3H), 6.34 (s, 1H),
2.31 ppm (s, 3H); 13C-NMR (125 MHz; DMSO-d6): δ = 161.5,
160.1, 152.2, 136.1, 130.3, 128.8, 127.9, 116.6, 106.5, 97.3,
19.1 ppm; HRMS (TOF) Calculated for C13H11N2O [M+H]+
211.0866, Found: 211.0869.
Scheme 1. Possible mechanism. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
6-Isopropyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile
(11g). (76% yield). 1H-NMR (500 MHz; DMSO-d6): δ = 12.55 (br
s, 1H), 7.63 (dd, J=6.6, 2.9Hz, 2H), 7.52–7.57 (m, 3H), 6.31 (s, 1H),
2.88 (spt, J= 6.9 Hz, 1H), 1.23 ppm (d, J= 7.1 Hz, 6H); 13C-NMR
(125 MHz; DMSO-d6): δ = 161.1, 161.3, 160.5, 136.2, 130.3,
128.8, 128.0, 116.5, 103.2, 97.9, 32.0, 20.9 ppm; HRMS (TOF)
Calculated for C15H15N2O [M+H]+ 239.1179, Found: 239.1188.
6-Ethyl-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-
carbonitrile (11h). (69% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 12.47 (br s, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.8 Hz,
2H), 6.31 (s, 1H), 3.83 (s, 3H), 2.57 (q, J = 7.3 Hz, 2H),
1.19 ppm (t, J = 7.5 Hz, 3H); 13C-NMR (125 MHz; DMSO-d6):
δ = 161.8, 161.0, 159.7, 156.8, 129.8, 128.1, 116.9, 114.2,
104.8, 96.7, 55.4, 26.1, 12.7 ppm; HRMS (TOF) Calculated for
C15H15N2O2 [M+H]+ 255.1128, Found: 255.1135.
4-(4-Chlorophenyl)-6-ethyl-2-oxo-1,2-dihydropyridine-3-
carbonitrile (11i). (72% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 12.64 (br s, 1H), 7.65 (d, J= 8.8 Hz, 2H), 7.61 (d, J=8.8Hz,
2H), 6.33 (s, 1H), 2.58 (q, J= 7.6 Hz, 2H), 1.19 ppm (t, J=7.6Hz,
3H); 13C-NMR (125 MHz; DMSO-d6): δ = 161.4, 159.1, 157.5,
135.2, 134.9, 129.9, 128.9, 116.4, 104.9, 97.7, 26.1, 12.6 ppm;
HRMS (TOF) Calculated for C14H12ClN2O [M+H]+ 259.0633,
Found: 259.0636.
98.4 ppm; HRMS (TOF) Calculated for C18H12ClN2O [M+H]+
307.0633, Found: 307.0642.
6-(4-Cyanophenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-
carbonitrile (11c). (51% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 8.12 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.75
(td, J = 3.8, 2.0 Hz, 2H), 7.56–7.60 (m, 3H), 7.05 ppm (br s, 1H);
13C-NMR (125 MHz; DMSO-d6): δ = 162.4, 159.4, 150.3, 137.1,
135.8, 132.7, 130.5, 128.8, 128.7, 128.4, 118.3, 116.2, 113.2,
108.2, 98.8 ppm; HRMS (TOF) Calculated for C19H12N3O [M+H]+
298.0975, Found: 298.0980.
6-(4-Chlorobenzyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-
carbonitrile (11d). (36% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 12.80 (br s, 1H), 7.56–7.60 (m, 2H), 7.52–7.55 (m, 3H), 7.42
(d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 6.37 (s, 1H),
3.93 ppm (s, 2H); 13C-NMR (125 MHz; DMSO-d6): δ = 161.5,
160.3, 153.8, 136.0, 135.7, 131.8, 130.9, 130.4, 128.8, 128.6,
127.9, 116.4, 106.3, 98.2, 37.6 ppm; HRMS (TOF) Calculated
for C19H14ClN2O [M+H]+ 321.0789, Found: 321.0791.
Methyl 4-(3-cyano-6-isopropyl-2-oxo-1,2-dihydropyridin-4-
yl)benzoate (11j). (69% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 12.66 (br s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz,
2H), 6.34 (s, 1H), 3.88 (s, 3H), 2.89 (dt, J = 13.7, 6.8 Hz, 1H),
1.23 ppm (d, J = 7.1 Hz, 6H); 13C-NMR (125 MHz; DMSO-d6):
6-Ethyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile
1
(11e). (82% yield). H-NMR (500MHz; DMSO-d6): δ = 12.50
(br s, 1H), 7.60–7.64 (m, 2H), 7.53–7.56 (m, 3H), 6.34 (s, 1H),
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Y. Wang, G. Liu, J. C. P. Reyes, and R. Duverna
Vol 000
δ = 165.6, 161.6, 161.4, 159.4, 140.6, 131.0, 129.4, 128.6, 116.2,
103.0, 98.2, 52.4, 32.0, 20.9 ppm; HRMS (TOF) Calculated for
C17H17N2O3 [M+H]+ 297.1234, Found: 297.1237.
6-Ethyl-5-methyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-
carbonitrile (13d). (69% yield). 1H-NMR (500 MHz; DMSO-d6):
δ = 12.53 (br s, 1H), 7.45–7.56 (m, 3H), 7.27–7.33 (m, 2H),
2.62 (q, J = 7.4 Hz, 2H), 1.73 (s, 3H), 1.15 ppm (t, J = 7.6 Hz,
3H); 13C-NMR (125 MHz; DMSO-d6): δ = 162.5, 160.1, 154.8,
136.4, 129.0, 128.7, 127.5, 115.7, 110.4, 100.4, 24.6, 13.4,
12.7 ppm; HRMS (TOF) Calculated for C15H15N2O [M+H]+
239.1179, Found: 239.1186.
Methyl 4-(3-cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridin-
1
4-yl)benzoate (11k).
(78% yield). H-NMR (500 MHz; DMSO-
d6): δ = 12.74 (br s, 1H), 8.06 (d, J= 8.6 Hz, 2H), 7.72 (d, J=8.3Hz,
2H), 6.07 (br s, 1H), 3.89 (s, 3H), 1.94–2.01 (m, J= 3.2 Hz, 1H),
1.14 (dt, J=8.3, 3.1Hz, 2H), 1.03–1.10 ppm (m, 2H); 13C-NMR
(125 MHz; DMSO-d6): δ = 165.7, 161.3, 159.6, 158.9, 140.7, 130.9,
129.3, 128.6, 116.4, 101.0, 96.3, 52.4, 13.8, 10.9 ppm; HRMS (TOF)
Calculated for C17H15N2O3 [M+H]+ 295.1077, Found: 295.1079.
6-Cyclohexyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile
(11l). (73% yield). 1H-NMR (500 MHz; DMSO-d6): δ = 12.52
(br s, 1H), 7.57–7.64 (m, 2H), 7.47–7.56 (m, 3H), 6.26 (s, 1H),
2.55 (dt, J = 12.0, 2.9 Hz, 1H), 1.82 (d, J = 11.7 Hz, 2H), 1.75
(d, J = 13.0 Hz, 2H), 1.64 (d, J = 12.0 Hz, 1H), 1.47 (qd, J = 12.3,
2.4 Hz, 2H), 1.09–1.33 ppm (m, 3H); 13C-NMR (125 MHz;
DMSO-d6): δ = 161.6, 160.4, 160.0, 136.2, 130.3, 128.8, 128.0,
116.5, 103.5, 97.8, 41.7, 30.8, 25.7, 25.0 ppm; HRMS (TOF)
Calculated for C18H19N2O [M+H]+ 279.1492, Found: 279.1491.
4-(4-Chlorophenyl)-6-cyclopropyl-2-oxo-1,2-dihydropyridine-
REFERENCES AND NOTES
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3-carbonitrile (11m).
(64% yield). 1H-NMR (500 MHz;
DMSO-d6): δ = 12.70 (br s, 1H), 7.62 (d, J = 8.6 Hz, 2H),
7.58 (d, J = 8.6 Hz, 2H), 6.03 (br s, 1H), 1.92–2.00 (m, 1H),
1.10–1.17 (m, 2H), 1.02–1.09 ppm (m, 2H); 13C-NMR
(125MHz; DMSO-d6): δ = 161.4, 159.3, 158.8, 135.1, 135.0,
130.0, 128.7, 116.6, 101.0, 96.2, 13.7, 10.8 ppm; HRMS (TOF)
Calculated for C15H12ClN2O [M+H]+ 271.0633, Found: 271.0640.
6-Cyclohexyl-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-
1
3-carbonitrile (11n). (59% yield). H-NMR (500 MHz; DMSO-
d6): δ = 12.33 (br s, 1H), 7.62 (d, J= 8.8 Hz, 2H), 7.09 (d, J=8.8Hz,
2H), 6.27 (s, 1H), 3.83 (s, 3H), 2.55 (dt, J= 12.0, 2.9 Hz, 1H),
1.72–1.87 (m, 4H), 1.66 (d, J = 12.2 Hz, 1H), 1.49 (qd, J = 12.3,
2.3 Hz, 2H), 1.28 ppm (d, J = 13.0 Hz, 3H); 13C-NMR (125 MHz;
DMSO-d6): δ = 161.8, 161.0, 159.8, 159.6, 129.8, 128.2, 116.9,
114.2, 103.4, 96.9, 55.4, 41.7, 30.8, 25.7, 25.0 ppm; HRMS (TOF)
Calculated for C19H21N2O2 [M+H]+ 309.1598, Found: 309.1603.
2-Oxo-4-phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-
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3-carbonitrile (13a).
(86% yield). 1H-NMR (500 MHz;
DMSO-d6): δ = 12.84 (br s, 1H), 7.50–7.56 (m, 3H), 7.45–7.50
(m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 6.8 Hz, 2H),
1.97 ppm (quin, J= 6.8 Hz, 2H); 13C-NMR (125 MHz; DMSO-d6):
δ = 161.7, 157.6, 157.1, 135.3, 129.7, 128.6, 127.8, 117.7, 116.9,
98.0, 31.6, 28.9, 22.0 ppm; HRMS (TOF) Calculated for
C15H13N2O [M+H]+ 237.1023, Found: 237.1031.
2-Oxo-4-phenyl-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile
(13b). (49% yield at RT; 89% yield at 80°C). 1H-NMR (500 MHz;
DMSO-d6): δ = 12.40 (br s, 1H), 7.45–7.55 (m, 3H), 7.28–7.33
(m, 2H), 2.63 (t, J= 6.4 Hz, 2H), 2.03 (t, J= 6.2 Hz, 2H), 1.62–1.71
(m, 2H), 1.50–1.59 ppm (m, 2v); 13C-NMR (125 MHz; DMSO-d6):
δ = 161.9, 159.8, 150.2, 135.5, 129.0, 128.7, 127.4, 116.1, 112.3,
100.4, 27.2, 24.9, 21.8, 20.6 ppm; HRMS (TOF) Calculated for
C16H15N2O [M+H]+ 251.1179, Found: 251.1182.
2-Oxo-4-phenyl-2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]
1
pyridine-3-carbonitrile (13c). (74% yield at 80 ˚C). H-NMR
(500 MHz; DMSO-d6): δ = 12.60 (br s, 1H), 7.43–7.57 (m, 3H),
7.20–7.32 (m, 2H), 2.78–2.87 (m, 2H), 2.19–2.28 (m, 2H), 1.71
(d, J = 4.9 Hz, 2H), 1.63 (d, J = 4.6 Hz, 2H), 1.35–1.43 ppm
(m, 2H); 13C-NMR (125 MHz; DMSO-d6): δ = 161.1, 160.0,
157.3, 136.4, 128.9, 128.7, 127.5, 118.3, 116.4, 99.2, 32.9,
31.0, 27.6, 26.6, 25.1 ppm; HRMS (TOF) Calculated for
C17H17N2O [M+H]+ 265.1336, Found: 265.1339.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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