One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides

Article abstract of DOI:10.1016/j.tet.2014.09.041

A one step, direct method for the synthesis of 1,5-diaryl pyridin-2(1H)-one derivatives by condensation of 2-aryl vinamidinium salts with N-aryl cyanoacetamides has been developed. This method can conveniently provide the corresponding 1,5-diaryl pyridin-

Full text of DOI:10.1016/j.tet.2014.09.041

Accepted Manuscript
One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and
N-aryl cyanoacetamides
Jiabin Yang, Guoqiang Su, Yu Ren, Yang Chen
PII:
S0040-4020(14)01330-1
10.1016/j.tet.2014.09.041
TET 26015
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 July 2014
Revised Date: 4 September 2014
Accepted Date: 15 September 2014
Please cite this article as: Yang J, Su G, Ren Y, Chen Y, One step synthesis of 1,5-diaryl pyridin-2(1H)-
ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides, Tetrahedron (2014), doi: 10.1016/
j.tet.2014.09.041.
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ACCEPTED MANUSCRIPT
One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from
2-aryl vinamidinium salts and N-aryl cyanoacetamides
Jiabin Yang,a Guoqiang Su,b Yu Renb and Yang Chen*a
aState Key Laboratory of Bioelectronics, School of Biological Science & Medical
Engineering, Southeast University, Nanjing, Jiangsu 210096, P.R. China
bNanjing Zhongrui Pharmaceutical Co., Ltd., Nanjing, Jiangsu 211100, P.R. China
*Corresponding author; Tel: +86 25 83790171; E-mail: yc@seu.edu.cn.
Abstract
A one step, direct method for the synthesis of 1,5-diaryl pyridin-2(1H)-one
derivatives by condensation of 2-aryl vinamidinium salts with N-aryl
cyanoacetamides has been developed. This method can conveniently provide the
corresponding 1,5-diaryl pyridin-2(1H)-one derivatives with various substituents in
good yields and overcome the drawbacks of existing methods such as poor substrate
scope, heavy metal pollution, and low yields. The formation mechanism of the
products was illustrated.
Keywords: N-aryl pyridin-2(1H)-one, perampanel, copper-catalyzed, Chan-Lam
coupling, Ullmann reaction, vinamidinium salt
1. Introduction
N-aryl pyridin-2(1H)-one is an important component of many biologically active
compounds,1 such as perampanel, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyri-
din-3-yl)-benzonitrile, which is the first α-amino-3-hydroxy-5-methyl-4-isoxazole-
propionic acid (AMPA) receptor inhibitor for the treatment of epilepsy and has been
approved by the European Medicines Agency and US FDA in 2012.2
Therefore, the synthesis of these compounds is an attractive subject in organic
chemistry. Conventionally, the formation of N-aryl pyridin-2(1H)-ones rely on the
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copper-catalyzed C-N coupling reactions,3 including Ullmann reaction4 and
Chan-Lam coupling reaction5 (Fig.1). The condensation of aryl halides with
pyridin-2(1H)-ones under the Ullmann reaction conditions usually require strong
bases, ligand acceleration and high temperatures, which often result in poor substrate
scope and low yields. Alternatively, the Chan-Lam coupling reaction using aryl
boronic acids instead of aryl halides react with pyridin-2(1H)-ones in the presence of
copper(II) acetate, oxygen and a base (such as pyridine) at room temperature. This
method could effectively avoid the strongly aggressive conditions of Ullmann
reaction, but the expensive aryl boronic acids as reaction substrates are necessary and
the aftertreatment of copper salts is very troublesome. More unfortunately, the
Chan-Lam coupling reaction has a reputation for erratic yields because of the effect of
ortho-substituents on aryl boronic acids.
Fig. 1 Traditional strategies for the synthesis of 3-cyano-1,5-diaryl pyridin-2(1H)-ones.
In recent years, some non-metal catalyzed methods for the preparation of N-aryl
pyridin-2(1H)-one derivatives have been reported (Scheme 1).1a, 1g, 6 Moreover, a
Diels-Alder reaction was also reported for the synthesis of these compounds.7
Although these methods are efficient, most of them suffer from significant limitations
such as the preconstruction of complex intermediates, high cost, or lack of selectivity.
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Scheme 1 Non-metal catalyzed methods for the preparation of N-aryl pyridin-2(1H)-one
derivatives.
We have been interested in building small molecules that contain the structure of
1,5-diaryl pyridin-2(1H)-one as possible therapeutic agents for human beings. When
the traditional methods were used to prepare the key intermediates 3-cyano-1,5-diaryl
pyridin-2(1H)-ones, N-free pyridin-2(1H)-ones were first synthesized, then the target
compounds were obtained by the condensation of N-free pyridin-2(1H)-ones and aryl
halides or aryl boronic acids. Although the N-free pyridin-2(1H)-ones could be easily
obtained by the condensation of 3-(dimethylamino)-2-aryl-2-propenal with
cyanoacetamide,8 the next step of either Chan-Lam coupling reaction or Ullmann
reaction was inefficient. Only a few reactions of aryl boronic acids with N-free
pyridin-2(1H)-ones could afford the corresponding products in moderate yields,
whereas the aryl halides didn’t produce the target compounds.
In view of these disappointing results, we proposed a novel, direct method for the
synthesis of 1,5-diaryl pyridin-2(1H)-ones by the reaction of 2-aryl vinamidinium
salts with N-aryl cyanoacetamides to avoid the C-N coupling reaction (Fig. 2).
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Fig. 2 Proposed strategy for the synthesis of 3-cyano-1,5-diaryl pyridin-2(1H)-ones.
2. Result and Discussion
In order to obtain optimal reaction conditions, (E)-N-(3-(dimethylamino)-2-phenyl-
allylidene)-N-methylmethanaminium perchlorate (1a) and 2-cyano-N-m-tolylacetami-
de (2c) were employed as the model substrates (Table 1). Different base-catalyzed
systems were evaluated. The mild bases such as pyridine, Et3N and K2CO3 cannot
trigger this reaction probably due to their alkalinity insufficient to remove the active
proton of 2c. Stronger basic systems (NaOEt/EtOH, t-BuOK/t-BuOH, NaH/DMF)
were tried. NaOEt/EtOH proved to be the most suitable basic system for this reaction
(entries 1-3). Further optimization of reaction conditions showed that more than 1.5
equivalent of NaOEt did not yield better results (entries 4 and 5). Finally, raising the
reaction temperature could shorten the reaction time (1 h), but the yield of 4ac
decreased significantly (42%, entry 6). It was found that the combination of 1.5
equivalent of NaOEt in anhydrous ethanol afford the product 4ac in the highest 77%
yield after stirring at room temperature for 24 h (entry 4). The reaction endpoint was
monitored by TLC and the product 4ac was isolated and confirmed by NMR and
HRMS.
Table 1 Synthesis conditions for the reaction of 1a with 2ca
Entry
Base (equiv)
Solvent
T (°C)
Time (h)
Yield (%)b
1
2
3
4
NaOEt (1.1)
t-BuOK (1.5)
NaH (2.2)
EtOH
t-BuOH
DMF
rt
24
2
65
0→rt
0→rt
rt
tracec
trace
77
0.5
24
NaOEt (1.5)
EtOH
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5
6
NaOEt (2.0)
NaOEt (1.5)
EtOH
EtOH
rt
24
1
74
42
reflux
a
b
Unless otherwise noted, all reactions were carried out with equimolar amounts of 1a and 2c.
Isolated yield. c monitored by TLC.
Having set up the reaction conditions, our attention was turned to investigate the
scope of application of this method. Firstly, the reactions of a variety of N-aryl
acetamides (2a-2l) with 1a were examined. As shown in Scheme 2, most of the
3-cyano-N-aryl pyridin-2(1H)-ones were obtained in good yields. The position of the
substituents on the phenyl ring of the N-aryl acetamides didn’t seem to play a role,
and similar yields (82% for 4ab, 77% for 4ac, and 78% for 4ad) were obtained from
corresponding substrates bearing a methyl group at para- (2b), meta- (2c), and
ortho-position (2d) of phenyl amines, respectively. The presence of
electron-withdrawing groups on aryl halides and aryl boronic acids could decrease the
reactivity of them, which usually resulted in poor yields of the Ullmann reaction and
the Chan-Lam reaction. Therefore, N-aryl acetamides substituted on the phenyl ring
with groups of different electronic properties were also explored, and excellent yields
were obtained in most cases. As depicted in Scheme 2, the substrates 2e and 2f
containing a nitro group (a strongly electron-withdrawing group) at the para- and
meta-position of the aniline gave the corresponding 3-cyano-N-aryl
pyridin-2(1H)-ones 4ae and 4af in 81% and 87% yields, respectively. The target
compound 4ag with a strongly electron-donating group (oxyethyl) at ortho-position of
aniline was obtained in 89% yield. And satisfactory yields of 4ah-4aj (81%, 87%, and
86%) were also obtained from the corresponding substrates 2h, 2i, and 2j with
electron-withdrawing groups, respectively. These results indicated that the electronic
properties of phenyl amines in N-aryl acetamides barely affected the reaction
pathway. Inexplicably, the 2-cyano-N-(2-cyanophenyl) acetamide 2k was found to
produce the product 4ak only in 46% yield. In addition, in order to determine whether
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this method is suitable for base-sensitive groups, we selected the ester group (2l) as
the model group for the reaction. A 73% yield of the corresponding
pyridin-2(1H)-one 4al suggested that the ester group was also well tolerated in this
method.
Scheme 2 Syntheses of 1-aryl-3-cyano-5-phenyl pyridin-2(1H)-ones from 1a and N-aryl
acetamides 2a-2l.
On these basis, we further explored the electronic properties of phenyl ring of the
other reaction partners, 2-aryl vinamidinium salts. Five substituted 2-aryl
vinamidinium salts (1b-1f) were selected and reacted with 2-cyano-N-m-tolylaceta-
mide 2c. As shown in Scheme 3, the very close yields for electron-rich substrates (1b
and 1c) and electron-deficient substrates (1d and 1e) showed that the
electron-donating substituents at the phenyl ring did not decrease the reactivity of
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vinamidinium salts.
Scheme 3 1-(3-methyl) phenyl-3-cyano-5-aryl pyridin-2(1H)-ones prepared from 1b-1f.
These results revealed that this approach was a general and efficient method for the
synthesis of 1,5-diaryl pyridin-2(1H)-ones except 4ak. We speculate that the reaction
mechanism is that the 2-cyano-N-(2-cyanophenyl) acetamide (2k) was first formed
the carbon-anion 2k’ in the presence of NaOEt, which could react with 2-aryl
vinamidinium salt 1 to generate the intermediate 3ak8, 9 and further underwent a
1,6-addition followed by an elimination of dimethylamine to yield the target
compound 4ak. On the other hand, the 2k’ may convert into the compound 4ak’
under an intramolecular nucleophilic cyclization reaction. Because of the competition
between the two reaction pathways, the yield of 4ak is much lower than other
compounds. In order to verify this hypothesis, the reaction mixture of 4ak was further
investigated. The molecular identification of the main byproduct 4ak’ in the reaction
mixture was consistent with the product of the mechanism (Scheme 4).
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Scheme 4 Proposed mechanism for the 4ak and 4ak’.
3. Conclusions
We have developed a direct, one step method for the synthesis of 1,5-diaryl
pyridin-2(1H)-one derivatives with the following advantages over previous syntheses:
1) No metal catalysts such as copper salts, have been used in the synthesis, avoiding
the heavy metal pollution. 2) Inexpensive and easily available starting materials,
2-aryl vinamidinium salts and N-aryl cyanoacetamides, were used. 3) One step
reaction with satisfactory yields in most cases. In addition, the reaction conditions
allowed the synthesis of some derivatives containing base sensitive groups such as
ester. We believed that the proposed synthesis method could make it possible that this
class of compounds prepared only in laboratory before because of the costliness can
be produced on a large-scale synthesis.
4. Experimental Section
4.1. General information
Unless otherwise specified, the commercial reagents were used as received without
further purification and all solvents were dried by standard methods prior to use.
NMR spectra were recorded on a 300 MHz or 500 MHz spectrometer. Shifts are
reported relative to tetramethylsilane; coupling constants (J) are given in hertz.
High-resolution mass spectral (HRMS) data were acquired using ESI-TOF detection.
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FTIR spectra were recorded on KBr thin film. Melting points were measured on a
WRS-2A melting point apparatus and are uncorrected. Column chromatography was
performed on silica gel (200-300 mesh) using CH2Cl2 and MeOH as eluent. N-aryl
cyanoacetamides were provided by our laboratory. 2-aryl vinamidinium salts (1a-1f)
were prepared according to the reported procedures.8 Caution: Although we observed
no explosive behavior with any of our perchlorate salts, it is still a potential hazard,
and adequate precautions should be used when drying and using them.
4.2. General Experimental Procedure for the Synthesis of 1,5-diaryl
pyridin-2(1H)-ones (4aa-4al, 4bc-4fc).
To a solution of NaOEt (3.0 mmol) in anhydrous ethanol (10 mL) were added
amide (2.0 mmol) and 2-aryl vinamidinium salt (2.0 mmol) at room temperature. The
reaction mixture was stirred at the same temperature for 24 h. After completion of the
reaction, the reaction mixture was poured into water (100 mL) to precipitate the crude
product, which was collected by filtration and washed with water. The residue was
purified by silica gel column chromatography (CH2Cl2: MeOH) to afford the
corresponding 1,5-diaryl-2-pyridone.
4.2.1. 2-oxo-1,5-diphenyl-1,2-dihydropyridine-3-carbonitrile (4aa): white solid (430
mg, 79%), m.p. 212-214 oC. 1H NMR (500 MHz, CDCl3):
7.80 (d, J = 3.0 Hz, 1H), 7.48-7.55 (m, 3H), 7.39-7.47 (m, 7H). 13C NMR (125 MHz,
DMSO-d6): 158.3, 147.5, 141.7, 139.6, 134.0, 129.0, 128.8 (d, J = 35 Hz), 127.5,
δ 8.16 (d, J = 3.0 Hz, 1H),
δ
126.7, 125.7 118.4, 116.1, 104.2. IR (KBr): ν 3449, 3056, 2226, 1662, 1611, 1535,
1495, 1453, 1276, 882, 760, 694 cm-1. HRMS (ESI-TOF): calcd. for C18H13N2O (M +
H)+ 273.1022, found 273.1024.
4.2.2. 2-oxo-5-phenyl-1-p-tolyl-1,2-dihydropyridine-3-carbonitrile (4ab): pale yellow
solid (470 mg, 82%), m.p. 200-202 oC. 1H NMR (300 MHz, DMSO-d6):
2.7 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 8.1 Hz,
δ 8.69 (d, J =
4H), 7.34 (t, J = 7.8 Hz, 3H), 2.38 (s, 3H). 13C NMR (125 MHz, DMSO-d6):
δ
158.3,
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147.4, 141.9, 138.5, 137.1, 134.0, 129.4, 128.8, 127.5, 126.4, 125.7, 118.3, 116.1,
104.0, 20.5. IR (KBr): ν 3443, 3063, 3047, 2226, 1670, 1594, 1529, 1501, 1451,
1402, 1290, 1276, 1114, 1085, 759, 694 cm-1. HRMS (ESI-TOF): calcd. for
C19H15N2O (M + H)+ 287.1179, found 287.1168.
4.2.3. 2-oxo-5-phenyl-1-m-tolyl-1,2-dihydropyridine-3-carbonitrile (4ac): pale yellow
o
1
solid (441 mg, 77%), m.p. 157-158 C. H NMR (300 MHz, CDCl3):
2.7 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.37-7.48 (m, 6H), 7.19-7.31 (m, 3H), 2.42 (s,
3H). 13C NMR (125MHz, DMSO-d6):
158.4, 147.6, 141.9, 139.6, 138.8, 134.1,
δ 8.15 (d, J =
δ
129.5, 128.8 (d, J = 15 Hz), 127.5, 127.2, 125.8, 123.8, 118.4, 116.2, 104.2, 20.7. IR
(KBr): ν 3446, 2223, 1682, 1607, 1533, 1489, 1452, 1291, 1277, 887, 874, 780, 757,
701, 691 cm-1. HRMS (ESI-TOF): calcd. for C19H15N2O (M + H)+ 287.1179, found
287.1186.
4.2.4. 2-oxo-5-phenyl-1-o-tolyl-1,2-dihydropyridine-3-carbonitrile (4ad): pale yellow
solid (447 mg, 78%), m.p. 206-208 oC. 1H NMR (300 MHz, DMSO-d6):
δ 8.76 (d, J =
2.7 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.31-7.44 (m, 7H),
13
2.11 (s, 3H). C NMR (125 MHz, DMSO-d6):
δ 158.0, 147.8, 142.0, 139.0, 134.5,
133.9, 130.7, 129.3, 128.8, 127.6, 127.4, 127.0, 125.8, 118.6, 116.1, 104.2, 17.1. IR
(KBr): ν 3446, 3037, 2224, 1666, 1530, 1494, 1451, 1273, 776, 761, 699 cm-1. HRMS
(ESI-TOF): calcd. for C19H15N2O (M + H)+ 287.1179, found 287.1187.
4.2.5. 1-(4-nitrophenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (4ae):
o
1
yellow solid (514 mg, 81%), m.p. 262-264 C. H NMR (300 MHz, DMSO-d6):
δ
8.76 (d, J = 2.7 Hz, 1H), 8.46 (d, J = 2.7 Hz, 1H), 8.41 (d, J = 9.0 Hz, 2H), 7.91 (d, J
= 9.0 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz,
1H). 13C NMR (125 MHz, DMSO-d6):
δ 158.1, 148.2, 147.3, 144.6, 141.2, 133.9,
128.9, 128.6, 127.7, 125.8, 124.3, 118.8, 115.9, 104.5. IR (KBr): ν 3451, 3111, 3087,
3059, 2230, 1666, 1614, 1524, 1492, 1351, 1317, 1278, 1107, 860, 766, 750, 699
cm-1. HRMS (ESI-TOF): calcd. for C18H12N3O3 (M + H)+ 318.0873, found 318.0877.
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4.2.6. 1-(3-nitrophenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (4af):
o
1
yellow solid (552 mg, 87%), m.p. 170-172 C. H NMR (300 MHz, DMSO-d6):
δ
8.76 (d, J = 2.7 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J = 2.7 Hz, 1H), 8.37 (dd, J = 8.4, 1.2
Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.71 (d, J = 8.7 Hz, 2H),
7.44 (t, J = 7.8 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H). 13C NMR (125 MHz, DMSO-d6):
δ
158.3, 148.1, 147.9, 141.7, 140.2, 133.9, 130.5, 128.9, 127.7, 125.8, 123.8, 122.6,
118.7, 116.0, 104.3. IR (KBr): ν 3454, 3072, 2237, 1678, 1605, 1529, 1452, 1354,
1290, 1271, 900, 826, 766, 736, 697 cm-1. HRMS (ESI-TOF): calcd. for C18H12N3O3
(M + H)+ 318.0873, found 318.0890.
4.2.7. 1-(2-ethoxyphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (4ag):
pale yellow solid (563 mg, 89%), m.p. 175-176 oC. 1H NMR (300 MHz, DMSO-d6):
δ
8.71 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.7 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.40-7.51
(m, 4H), 7.34 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H),
4.10 (q, J = 6.9 Hz, 2H), 1.20 (t, J = 6.9 Hz, 3H). 13C NMR (125 MHz, DMSO-d6):
δ
158.1, 153.0, 147.8, 143.0, 134.0, 130.7, 128.9, 128.5, 127.5, 125.6, 120.5, 118.0,
116.2, 113.8, 104.0, 64.2, 14.4. IR (KBr): ν 3446, 3040, 2977, 2224, 1671, 1601,
1535, 1500, 1452, 1278, 1247, 1130, 1043, 894, 770, 750, 696 cm-1. HRMS
(ESI-TOF): calcd. for C20H17N2O2 (M + H)+ 317.1285, found 317.1288.
4.2.8. 1-(4-chlorophenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (4ah):
white solid (503 mg, 82%), m.p. 222-224 oC. 1H NMR (300 MHz, DMSO-d6):
δ 8.72
(d, J = 2.7 Hz, 1H), 8.39 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 7.2 Hz, 2H), 7.62 (s, 4H),
13
7.43 (t, J = 7.8 Hz, 2H), 7.35(d, J = 7.2 Hz, 1H). C NMR (125 MHz, DMSO-d6):
δ
158.2, 147.7, 141.6, 138.2, 133.9, 133.5, 129.0, 128.7 (d, J = 35 Hz), 127.5, 125.7,
118.5, 116.0, 104.2. IR (KBr): ν 3445, 3083, 3055, 2226, 1664, 1616, 1530, 1486,
1317, 1274, 1089, 1011, 907, 834, 767, 698 cm-1. HRMS (ESI-TOF): calcd. for
C18H12ClN2O (M + H)+ 307.0633, found 307.0642.
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4.2.9. 1-(3-chlorophenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (4ai):
white solid (515 mg, 84%), m.p. 188-190 oC. 1H NMR (300 MHz, DMSO-d6):
δ 8.72
(d, J = 2.7 Hz, 1H), 8.42 (d, J = 2.7 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H),
13
7.55-7.60 (m, 3H), 7.43 (t, J = 7.8 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H). C NMR (125
MHz, DMSO-d6):
δ 158.2, 147.8, 141.6, 140.6, 133.9, 133.1, 130.5, 128.8 (d, J = 80
Hz), 127.5, 127.1, 125.8, 118.5, 115.9, 104.2. IR (KBr): ν 3446, 3089, 3030, 2219,
1671, 1591, 1531, 1473, 1283, 868, 789, 767, 697 cm-1. HRMS (ESI-TOF): calcd. for
C18H12ClN2O (M + H)+ 307.0633, found 307.0632.
4.2.10. 1-(2-chloro-5-nitrophenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonit-
o
1
rile (4aj): yellow solid (605 mg, 86%), m.p. 243-245 C. H NMR (300 MHz,
DMSO-d6): 8.84 (d, J = 2.7 Hz, 1H), 8.77 (d, J = 2.7 Hz, 1H), 8.55 (d, J = 2.4 Hz,
δ
1H), 8.43 (dd, J = 8.9, 2.4 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H),
13
7.46 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H). C NMR (75 MHz, DMSO-d6):
δ
157.7, 148.8, 146.7, 141.7, 138.2, 137.7, 133.7, 131.3, 129.0, 127.8, 125.8, 125.7,
125.4, 118.9 115.7, 104.4. IR (KBr): ν 3456, 3095, 2228, 1663, 1528, 1352, 1284,
901, 840, 766, 741, 694 cm-1. HRMS (ESI-TOF): calcd. for C18H11ClN3O3 (M + H)+
352.0483, found 352.0485.
4.2.11. 1-(2-cyanophenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (4ak):
o
1
yellow solid (274 mg, 46%), m.p. 248-254 C. H NMR (300 MHz, DMSO-d6):
δ
8.85 (d, J = 2.7 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.96 (t, J =
7.8 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.71-7.79 (m, 3H), 7.46 (t, J = 7.5 Hz, 2H),
7.35-7.40 (m, 1H). 13C NMR (125 MHz, DMSO-d6):
δ 158.0, 148.9, 141.6, 141.3,
134.7, 133.6 (d, J = 90 Hz), 130.2, 129.0, 127.9, 125.8, 118.9, 115.7 (d, J = 45 Hz),
111.0, 104.3. IR (KBr): ν 3454, 3083, 3058, 2229, 1676, 1620, 1530, 1491, 1452,
1291, 1270, 904, 766, 703 cm-1. HRMS (ESI-TOF): calcd. for C19H12N3O (M + H)+
298.0975, found 298.0985.
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4.2.12. ethyl 4-(3-cyano-2-oxo-5-phenylpyridin-1(2H)-yl)benzoate (4al): yellow solid
o
1
(502 mg, 73%), m.p. 230-232 C. H NMR (300 MHz, DMSO-d6):
δ 8.75 (d, J = 2.7
Hz, 1H), 8.42 (d, J = 2.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H),
7.71 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.33-7.38 (m, 1H), 4.37 (q, J = 7.2
13
Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). C NMR (75 MHz, DMSO-d6):
δ 164.9, 158.2,
148.0, 143.3, 141.5, 134.0, 130.2, 129.9, 128.9, 127.7, 127.4, 125.9, 118.7, 116.0,
104.3, 61.0, 14.1. IR (KBr): ν 3455, 2233, 1714, 1676, 1282, 1130, 1108, 865, 758
cm-1. HRMS (ESI-TOF): calcd. for C21H17N2O3 (M + H)+ 345.1234, found 345.1242.
4.2.13. 2-oxo-1-m-tolyl-5-p-tolyl-1,2-dihydropyridine-3-carbonitrile (4bc): yellow
solid (499 mg, 83%), m.p. 188-190 oC. 1H NMR (300 MHz, DMSO-d6):
δ 8.67 (d, J =
2.7 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 7.5 Hz,
1H), 7.33 (t, J = 7.5 Hz, 3H), 7.22 (d, J = 8.1 Hz, 2H), 2.38 (s, 3H), 2.31 (s, 3H). 13C
NMR (125 MHz, DMSO-d6):
δ 158.3, 147.4, 141.4, 139.6, 138.7, 136.9, 131.1, 129.4
(d, J = 35 Hz), 128.9, 127.2, 125.6, 123.8, 118.4, 116.2, 104.1, 20.7, 20.5. IR (KBr): ν
3453, 3036, 2968, 2923, 2223, 1674, 1611, 1531, 1487, 1453, 1288, 874, 812, 778,
767, 701 cm-1. HRMS (ESI-TOF): calcd. for C20H17N2O (M + H)+ 301.1335, found
301.1346.
4.2.14.
(4cc): yellow solid (557 mg, 88%), m.p. 176-178 oC. 1H NMR (300 MHz, DMSO-d6):
8.64 (d, J = 2.7 Hz, 1H), 8.26 (d, J = 2.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.43 (t, J
= 7.5 Hz, 1H), 7.33 (t, J = 7.2 Hz, 3H), 6.97 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 2.39 (s,
3H). 13C NMR (125 MHz, DMSO-d6):
158.9, 158.2, 147.4, 140.9, 139.6, 138.7,
5-(4-methoxyphenyl)-2-oxo-1-m-tolyl-1,2-dihydropyridine-3-carbonitrile
δ
δ
129.4, 128.8, 127.1 (d, J = 40Hz), 126.4, 123.8, 118.3, 116.2, 114.2, 104.1, 55.1, 20.7.
IR (KBr): ν 3450, 2930, 2835, 2220, 1664, 1613, 1522, 1456, 1287, 1254, 1183,
1030, 830, 800, 765, 705 cm-1. HRMS (ESI-TOF): calcd. for C20H17N2O2 (M + H)+
317.1285, found 317.1282.
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4.2.15. 5-(4-chlorophenyl)-2-oxo-1-m-tolyl-1,2-dihydropyridine-3-carbonitrile (4dc):
white solid (545 mg, 85%), m.p. 192-194 oC. 1H NMR (300 MHz, DMSO-d6):
δ 8.71
(d, J = 2.7 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4
13
Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H). C NMR
(125 MHz, DMSO-d6):
δ 158.3, 147.4, 142.2, 139.5, 138.7, 133.0, 132.3, 129.5, 128.8
(d, J = 75 Hz), 127.6, 127.1, 123.8, 117.2, 116.0, 104.1, 20.7. IR (KBr): ν 3446, 3062,
3038, 2914, 2233, 1665, 1619, 1533, 1490, 1277, 1092, 894, 831, 789, 769, 706 cm-1.
HRMS (ESI-TOF): calcd. for C19H14ClN2O (M + H)+ 321.0789, found 321.0794.
4.2.16. 5-(4-nitrophenyl)-2-oxo-1-m-tolyl-1,2-dihydropyridine-3-carbonitrile (4ec):
o
1
yellow solid (603 mg, 91%), m.p. 270-272 C. H NMR (300 MHz, DMSO-d6):
δ
8.85 (d, J = 2.7 Hz, 1H), 8.62 (d, J = 2.7 Hz, 1H), 8.25 (d, J = 9.0 Hz, 2H), 8.02 (d, J
13
= 9.0 Hz, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.34-7.39 (m, 3H), 2.39 (s, 3H). C NMR
(125 MHz, DMSO-d6):
δ 158.3, 147.4, 146.4, 143.7, 140.8, 139.4, 138.8, 129.6,
128.9, 127.2, 126.7, 123.8 (d, J = 15Hz), 116.0 (d, J = 85Hz), 104.3, 20.7. IR (KBr): ν
3454, 3084, 2919, 2227, 1678, 1598, 1513, 1343, 1319, 1283, 1212, 1112, 853, 781,
754 cm-1. HRMS (ESI-TOF): calcd. for C19H14N3O3 (M + H)+ 332.1030, found
332.1031.
4.2.17. 5-(4-fluorophenyl)-2-oxo-1-m-tolyl-1,2-dihydropyridine-3-carbonitrile (4fc):
pale yellow solid (408 mg, 67%), m.p. 172-173 oC. 1H NMR (300 MHz, DMSO-d6):
δ
8.70 (d, J = 2.7 Hz, 1H), 8.37 (d, J = 2.7 Hz, 1H), 7.73-7.78 (m, 2H), 7.45 (t, J = 7.5
Hz, 1H), 7.32-7.37 (m, 3H), 7.27 (t, J = 8.7 Hz, 2H), 2.39 (s, 3H). 13C NMR (125
MHz, DMSO-d6):
δ 162.7, 160.8, 158.3, 147.6, 141.9, 139.5, 138.7, 130.57 (d, J = 10
Hz), 129.5, 128.8, 128.0 (d, J = 30 Hz), 127.2, 123.8, 117.5, 116.1, 115.6 (d, J = 85
Hz), 104.0, 20.7. IR (KBr): ν 3445, 3027, 2222, 1664, 1614, 1508, 1271, 1229, 833,
769, 698 cm-1. HRMS (ESI-TOF): calcd. for C19H14FN2O (M + H)+ 305.1085, found
305.1087.
4.2.18. 4-amino-2-oxo-1,2-dihydroquinoline-3-carbonitrile (4ak’). Purified by
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o
recrystallization from DMF/EtOAc; White solid (137 mg), m.p. 284-287 C (Lit.10
o
1
321-323 C). H NMR (300 MHz, DMSO-d6):
1H), 7.86 (br.s, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.5
Hz, 1H). 13C NMR (125 MHz, DMSO-d6):
160.7, 158.4, 139.5, 133.0, 123.7, 121.5,
δ 11.22 (s, 1H), 8.12 (d, J = 8.1 Hz,
δ
116.7, 116.2, 111.4, 77.6. IR (KBr): ν 3384, 3332, 3229, 3011, 2220, 1630, 1597,
1508, 1458, 1415, 1364, 754 cm-1. HRMS (ESI-TOF): calcd. for C10H8N3O (M + H)+
186.0662, found 186.0663; calcd. for C10H7N3ONa (M + Na)+ 208.0481, found
208.0478.
Acknowledgments
This work was supported by the National Natural Science Foundation of China
(NSFC) with the grant numbers of 60671014 and 20775012.
Supplementary data
1
Electronic Supplementary Information (ESI) available: Copies of the H NMR and
13C NMR spectra for all final products of 4aa-4al, 4bc-4fc and the compound 4ak’.
References and notes
1 (a) Kim, K. S.; Zhang, L.; Schmidt, R.; Cai, Z. W.; Wei, D.; Williams, D. K.;
Lombardo, L. J.; Trainor, G. L.; Xie, D.; Zhang, Y.; An, Y.; Sack, J. S.; Tokarski,
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Borzilleri, R. M. J. Med. Chem. 2008, 51, 5330-5341; (b) Tamura, Y.; Omori, N.;
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Yukioka, H.; Sato, H.; Okuno, T. Bioorg. Med. Chem. Lett. 2012, 22, 5498-5502;
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(c) Allen, J. G.; Lee, M. R.; Han, C.-Y. E.; Scherrer, J.; Flynn, S.; Boucher, C.;
Zhao, H.; O'Connor, A. B.; Roveto, P.; Bauer, D.; Graceffa, R.; Richards, W. G.;
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Y.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T. S. J. Nat. Prod. 2009, 72,
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Jeyaseelan, R.; Kamath, A.; Kim, K.; Lippy, J.; Lombardo, L. J.; Manne, V.;
Oppenheimer, S.; Sack, J. S.; Schmidt, R. J.; Shen, G.; Stefanski, K.; Tokarski, J.
S.; Trainor, G. L.; Wautlet, B. S.; Wei, D.; Williams, D. K.; Zhang, Y.; Fargnoli,
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Y.; Meagher, K. L.; Whittington, D. A.; Ng, G. Y. J. Med. Chem. 2008, 51,
3065-3068; (g) Lv, Z.; Sheng, C.; Wang, T.; Zhang, Y.; Liu, J.; Feng, J.; Sun, H.;
Zhong, H.; Niu, C.; Li, K. J. Med. Chem. 2010, 53, 660-668.
2 (a) Hibi, S.; Ueno, K.; Nagato, S.; Kawano, K.; Ito, K.; Norimine, Y.; Takenaka,
O.; Hanada, T.; Yonaga, M. J. Med. Chem. 2012, 55, 10584-10600; (b) Shvarts,
V.; Chung, S. Expert Rev. Neurother. 2013, 13, 131-134.
3 Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054-3131.
4 (a) Wang, P.-S.; Liang, C.-K.; Leung, M.-k. Tetrahedron. 2005, 61, 2931-2939; (b)
Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863-3867; (c) Zhu, L.; Cheng, L.;
Zhang, Y.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 2737-2743; (d) Jammi, S.;
Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, P.;
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2933-2936; (c) McElhinny Jr, C. J.; Carroll, F.; Lewin, A. H. Synthesis. 2012, 44,
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Graphical Abstract
O
B
A
NC
N
ClO4
N
O
NaOEt
EtOH, 24 h, r.t.
A
N
+
NC
N
H
B
1,5-diaryl pyridin-2(1H)-ones
2-aryl vinamidinium salts N-aryl cyanoacetamides
A simple, non-metal catalyzed method has been developed for the synthesis of
1,5-diaryl pyridin-2(1H)-one derivatives in good yields.
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Supplementary Material
One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium
salts and N-aryl cyanoacetamides
Jiabin Yang,a Guoqiang Su,b Yu Renb and Yang Chen*a
State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast
University, Nanjing, Jiangsu 210096, P.R. China
bNanjing Zhongrui Pharmaceutical Co., Ltd., Nanjing, Jiangsu 211100, P.R. China
List of 1H NMR and 13C NMR spectra for compounds 4aa-4al, 4bc-4fc and 4ak’
Page S2··········································································1H NMR and 13C NMR of 4aa
Page S3··········································································1H NMR and 13C NMR of 4ab
Page S4··········································································1H NMR and 13C NMR of 4ac
Page S5··········································································1H NMR and 13C NMR of 4ad
Page S6··········································································1H NMR and 13C NMR of 4ae
Page S7··········································································1H NMR and 13C NMR of 4af
Page S8··········································································1H NMR and 13C NMR of 4ag
Page S9··········································································1H NMR and 13C NMR of 4ah
Page S10········································································1H NMR and 13C NMR of 4ai
Page S11········································································1H NMR and 13C NMR of 4aj
Page S12········································································1H NMR and 13C NMR of 4ak
Page S13········································································1H NMR and 13C NMR of 4al
Page S14········································································1H NMR and 13C NMR of 4bc
Page S15········································································1H NMR and 13C NMR of 4cc
Page S16········································································1H NMR and 13C NMR of 4dc
Page S17········································································1H NMR and 13C NMR of 4ec
Page S18········································································1H NMR and 13C NMR of 4fc
Page S19········································································1H NMR and 13C NMR of 4ak’
S1

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1H NMR and 13C NMR of 4aa
O
NC
N
4aa
S2

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1H NMR and 13C NMR of 4ab
S3

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1H NMR and 13C NMR of 4ac
S4

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1H NMR and 13C NMR of 4ad
S5

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1H NMR and 13C NMR of 4ae
S6

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1H NMR and 13C NMR of 4af
S7

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1H NMR and 13C NMR of 4ag
S8

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1H NMR and 13C NMR of 4ah
S9

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1H NMR and 13C NMR of 4ai
S10

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1H NMR and 13C NMR of 4aj
Cl
O
NC
N
NO2
4aj
S11