Novel construction of diversely functionalized: N -heteroaryl-2-pyridones via copper(II)-catalyzed [3+2+1] annulation

Article abstract of DOI:10.1039/c7nj03013d

A facile and novel one-pot construction of diversely functionalized N-heteroaryl-2-pyridones is achieved by Cu(OTf)₂-catalyzed [3+2+1] annulation of various 2-aminopyridines and β-enamino esters. The [3+2+1] annulation proceeds via domino two Michael additions/elimination/isomerization/intramolecular cyclization.

Full text of DOI:10.1039/c7nj03013d

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Novel construction of diversely functionalized
N-heteroaryl-2-pyridones via copper(II)-catalyzed
[3+2+1] annulation†
Cite this:DOI: 10.1039/c7nj03013d
a
a
b
Muhammad Saeed Akhtar,
Jae-Jin Shim,
Sung Hong Kim
and
a
Yong Rok Lee
*
Received 14th August 2017,
Accepted 4th October 2017
A
facile and novel one-pot construction of diversely functionalized N-heteroaryl-2-pyridones is
achieved by Cu(OTf)2-catalyzed [3+2+1] annulation of various 2-aminopyridines and b-enamino esters.
The [3+2+1] annulation proceeds via domino two Michael additions/elimination/isomerization/intramolecular
cyclization.
DOI: 10.1039/c7nj03013d
rsc.li/njc
formation of N-alkenyl alkynylamides followed by gold-catalyzed
Introduction
cycloisomerization,24 nucleophilic addition of malonic esters to
2-Pyridone derivatives are important heterocyclic scaffolds, alkynyl imines,25 and Rh(III)-catalyzed C–H activation/annulation
which constitute the core of a large number of natural alkaloids, of N-methoxy methacrylamides with diazo compounds.26 Despite
pharmaceuticals, and agrochemicals (Fig. 1).1 2-Pyridone-based these reports, more facile and efficient strategies are still highly
molecules possess a wide spectrum of biological properties like desirable. This prompted us to develop a new methodology based
antimalarial,2 antimicrobial,3 vasorelaxant,4 antiasthma,5 anti- on the characteristic reactivity of 2-aminopyridines. Recently,
epilepsy,6 anti-HIV,7 antitumor,8 anti-hepatitis B,9 antioxidant,10 N-heteroaryl-2-pyridones have received significant attention
antiviral,11 and antituberculosis activities.12 Some of them are because of their versatile applications in organic synthesis.27
currently used as pharmaceuticals for the treatment of idiopathic Among the applications of N-heteroaryl-2-pyridones, the metal-
pulmonary fibrosis (Pirfenidone, sPirfenex, sPirespa, sEsbriet, catalyzed direct C–H functionalization reactions of 1-(2-pyridyl)-2-
and Etuary),13 congestive heart failure (Milrinone, sPrimacor),14 pyridones with 1,3-azoles,27a bis(pinacolato)-diboron,27b alkyltri-
and epileptic seizures (Perampanel, sFycompa).15 They are also fluoroborates,27c propargyl alcohols,27d anthranil,27e and diazo
used as building blocks for the synthesis of bioactive and functional compounds27f have been well described. Nevertheless, only a few
materials.16 Moreover, the versatile nature of 2-pyridones enables synthetic routes to N-heteroaryl-2-pyridones have been reported,
their transformation into structurally important heterocyclic which include the copper-catalyzed coupling reaction of
scaffolds such as pyridines,17 piperidines,18 b-lactams,19 indoli- 2-pyridones with heteroaryl halides.28 To the best of our knowl-
zidines, and quinolizidines.20
edge, there is no report on the direct synthesis of N-heteroaryl-2-
Owing to the importance and usefulness of 2-pyridones, pyridones from readily available 2-aminopyridines via an annulation
various approaches for their construction have been reported,
including transition-metal-catalyzed [2+2+2] cycloaddition of
1,6-diynes with isocyanates (eqn (1), Scheme 1),21 oxidative
coupling between acrylamides and alkynes (eqn (2), Scheme 1),22
1,4-addition of 2-(phenylsulfinyl)acetamide to a,b-unsaturated
ketones followed by cyclization and sulfoxide elimination,23
a School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749,
Republic of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631;
Tel: +82-53-810-2529
b Analysis Research Division, Daegu Center, Korea Basic Science Institute,
Daegu 702-701, Republic of Korea
† Electronic supplementary information (ESI) available: 1H NMR and 13C NMR spectra
Fig. 1 Selected pharmaceuticals (a) and bioactive natural products
for synthesized compounds. X-ray structure. CCDC 1534635 (3n). For ESI and crystal-
(b) containing the 2-pyridone moiety.
lographic data in CIF or other electronic format see DOI: 10.1039/c7nj03013d
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Table 1 Optimization of the synthesis of 2-pyridone 3aa
Temp. Time Yieldb
Entry Catalyst
Solvent
(1C)
(h)
(%)
Scheme 1 Representative methods for the synthesis of 2-pyridones.
1
2
3
4
5
6
7
8
AgOAc (10 mol%)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
r.t.
24
0
0
AgOAc (10 mol%)
AgOTf (10 mol%)
Yb(OTf)3 (10 mol%)
Sc(OTf)3 (10 mol%)
lnCI3 (10 mol%)
lnBr3 (10 mol%)
ln(OTf)3 (10 mol%)
Cu(OTf)2 (10 mol%) Toluene
Cu(OTf)2 (5 mol%) Toluene
Cu(OTf)2 (20 mol%) Toluene
Cu(OTf)2 (10 mol%) THF
Reflux 24
Reflux 24
Reflux 24
Reflux 24
Reflux 24
Reflux 15
Reflux 15
Reflux 10
Reflux 10
Reflux 10
Reflux 10
18
23
25
30
48
51
72
63
71
15
23
52
48
0
9
Scheme 2 Novel N-heteroaryl-2-pyridone construction via [3+2+1]
annulation.
10
11
12
13
14
15
16
17
18
19
20c
21
Cu(OTf)2 (10 mol%) 1,4-Dioxane Reflux 10
strategy, which have been mainly used as key starting materials for
the preparation of bioactive imidazo[1,2-a]pyridines.29
Cu(OTf)2 (10 mol%) CHCI3
Cu(OTf)2 (10 mol%) CH3CN
Cu(OTf)2 (10 mol%) EtOH
Cu(OTf)2 (10 mol%) Toluene
Cu(OTf)2 (10 mol%) Toluene
TfOH (10 mol%)
Cu(OTf)2 (10 mol%) Toluene
CuCI2 (10 mol%) Toluene
Reflux 10
Reflux 10
Reflux 10
r.t.
70
Reflux 24
Reflux 24
Reflux 24
Recently, we have reported the construction of heterocycles
and aromatics such as polyfunctionalized pyridines, chromeno-
pyridinones, carbazoles, biaryls, anthraquinones, and 2-hydroxy-
benzophenones via N-annulation and benzannulation reactions.30
In addition, we have developed an eco-friendly synthesis of
2-pyridones by catalyst- and solvent-free thermal multicomponent
domino reaction.31 As the result of our continued interest in this
area, herein we report a simple and efficient methodology for the
construction of biologically important N-heteroaryl-2-pyridones
from readily available 2-aminopyridines (Scheme 2). This is the
first example of the direct construction of diversely functionalized
N-heteroaryl-2-pyridones via Cu(OTf)2-catalyzed [3+2+1] annulation
of 2-aminopyridines with b-enamino esters.
10
24
0
10
26
69
64
Toluene
a
Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol) and solvent (5.0 mL).
b Isolated yield after column chromatography. c Proton sponge (20 mol%).
increasing it to 20 mol% did not improve the yield (entries
10 and 11). In nonpolar solvents of THF, 1,4-dioxane, and
chloroform, 3a was produced in 15, 23, and 52% yield, respectively
(entries 12–14). In polar aprotic acetonitrile, 3a was isolated in
48% yield, whereas in polar protic ethanol, 3a was not obtained
at all (entries 15 and 16). Effect of temperature showed no
improvement in yield of product 3a when studied at room
temperature and 70 1C (entries 17 and 18). In order to investi-
gate the role of in situ generated triflic acid, the reaction was
Results and discussion
To optimize the reaction conditions, the reaction of 2-amino- carried out with TfOH instead of Cu(OTf)2 as the catalyst. With
pyridine (1a) with methyl (E)-3-(dimethylamino)acrylate (2a) 10 mol% of triflic acid in refluxing toluene for 24 h, product 3a
was investigated using various metal catalysts and solvents was formed but in lower yield of 26% (entry 19). In addition,
(Table 1). Lewis acids are well-known for the conjugate addition with 20 mol% of proton sponge and 10 mol% of Cu(OTf)2, 3a
of amines to a,b-unsaturated carbonyl compounds. Hence, was isolated in 69% yield (entry 20). From this result, TfOH
several Lewis acids were screened for conjugate addition of generated in situ has no significant role in this transformation.
aminopyridines to b-enamino esters to form heterocyclics. This was further confirmed by using other non-triflate-based
Toluene is predominantly used as a solvent in cycloaddition. copper catalyst CuCl2 which gave the product 3a in 64% yield
Initially, treatment of 1a (1.0 mmol) with 2a (2.0 mmol) in the (entry 21). The structure of 3a was established by analysis of its
presence of 10 mol% AgOAc in toluene at room temperature or spectral data. The 1H NMR spectrum exhibited peaks corres-
at reflux for 24 h did not provide the product 3a (entries 1 and ponding to the 2-pyridone ring: the singlet at d 3.85 ppm was
2); however, using 10 mol% AgOTf in refluxing toluene for 24 h, attributed to the methoxy protons, two vinyl protons appeared at
product 3a was isolated in 18% yield (entry 3). Encouraged by d 6.60 and 7.85 ppm as two doublets ( J = 9.6 Hz), and one vinyl
this result, other catalysts were tested. When the reaction was proton appeared at 8.72 ppm as a singlet. The 13C NMR showed
performed in the presence of the rare-earth metal catalysts the characteristic methoxy carbon signal at d 52.0 ppm and
Yb(OTf)3, Sc(OTf)3, InCl3, InBr3, and In(OTf)3 in refluxing carbonyl carbon signals of the ester and amide groups at d 164.7
toluene for 15–24 h, 3a was formed in 23, 25, 30, 48, and and 161.8 ppm, respectively. Based on the X-ray analysis of
51% yield, respectively (entries 4–8). The best yield (72%) was structurally related compound 3n (vide infra), the structure of 3a
achieved with 10 mol% Cu(OTf)2 in refluxing toluene for 10 h was confirmed in analogy. The ellipsoidal probability for crystal
(entry 9). Decreasing the Cu(OTf)2 loading to 5 mol% or structure 3n is 50%.
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With the optimized conditions in hand, we explored the
Paper
Table 3 Formation of diverse 2-pyridones 4a–4h by the reaction of 1g or
1h with 2a–2da,b
scope of 2-aminopyridines and b-enamino esters for the synthesis
of N-heteroaryl-2-pyridones, and the results are depicted in
Table 2. Treatment of 1a with 2b, 2c, or 2d bearing an ethyl,
prenyl, or benzyl substituent provided the corresponding
products 3b–3d in 75, 54, and 65% yield, respectively. When
b-enamino ester 2e bearing a 2-naphthyl group was used,
compound 3e was formed in 49% yield. The reactions of
1b–1f bearing electron-donating or -withdrawing substituents
on the pyridine ring were also successful. For example, the
combination of 2-aminopyridine 1b, 1c, 1d, or 1e bearing the
electron-donating 3-benzyloxy, 4-methyl, 4-methoxy, or 4,6-
dimethyl group, respectively, with b-enamino esters 2a–2d
provided the desired products 3f–3p in 57–78% yield. Similarly,
treatment of 1e bearing the electron-withdrawing 4-Cl group
with b-enamino esters 2a–2d afforded products 3q–3t in 53, 59,
45, and 55% yield, respectively. This protocol provides a rapid
synthetic route to N-(20-pyridyl)-2-pyridone derivatives bearing a
variety of substituents on the 2-pyridone ring in a one-pot fashion.
To demonstrate the versatility of this strategy, we further
examined the reactions of 2-aminoquinoline (1g) and 3-amino-
isoquinoline (1h) with b-enamino esters 2a–2d (Table 3).
Compound 1g reacted with 2a, 2b, 2c, or 2d in refluxing toluene
for 10 h to give products 4a–4d in 68–83% yield. Similarly, the
combination of 1h with b-enamino esters 2a–2d successfully
afforded the corresponding products 4e–4h in 67–80% yield.
Next, we explored the annulation reaction of the two-nitrogen-
based nucleophiles 3-aminopyridazine (1i), 2-aminopyrazine (1j),
a
Reaction conditions: aminoquinolines (1.0 mmol), b-enamino esters
b
(2.0 mmol), Cu(OTf)2 (10 mol%) in toluene (5.0 mL). Isolated yield
after column chromatography.
and 2-aminopyrimidine (1k) (Table 4). To our delight, the reaction
of 1i with b-enamino ester 2a, 2b, 2c, or 2d afforded the corres-
ponding products 5a–5d in 32–54% yield. Similarly, treatment of 1j
with 2a, 2b, or 2d successfully provided products 5e–5g in 53, 61,
and 51% yield, respectively, whereas the reaction of 1k with 2a or
2b afforded product 5h or 5i in 58 and 55% yield, respectively.
Control experiments were carried out to understand the
mechanism for the formation of 3a (Scheme 3). The reaction
Table 2 Formation of diverse N-20-pyridyl-2-pyridones 3b–3t by the
reaction of 1a–1f with 2a–2ea,b
Table 4 Formation of diverse 2-pyridones 5a–5i by the reaction of 1j, 1k,
or 1l with 2a–2da,b
a
a
Reaction conditions: 2-amino pyridines (1.0 mmol), b-enamino ester
Reaction conditions: 2-amino derivatives (1.0 mmol), b-enamino
b
b
(2.0 mmol), and Cu(OTf)2 (10 mol%) in toluene (5.0 mL). Isolated esters (2.0 mmol), Cu(OTf)2 (10 mol%) in toluene (5.0 mL). Isolated
yield after column chromatography.
yield after column chromatography.
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catalyst generates copper complex 12, which is cyclized by
intramolecular nucleophilic addition of the amino group to
the electrophilic carbonyl carbon to yield final product 3a. In
case of aniline, formation of Cu-complex is not possible due to
the absence of coordinating N-atom in the ring. Therefore, only
uncyclized product 9 was formed instead of annulated product
8 (eqn (3), Scheme 3).
Conclusions
In conclusion, we have developed a highly efficient Cu(OTf)2-
catalyzed one-pot protocol for the synthesis of diversely function-
alized N-heteroaryl-2-pyridones starting from readily available
2-aminopyridines and b-enamino esters via [3+2+1] annulation.
This methodology provides a novel synthetic approach for the
construction of 2-pyridone derivatives bearing a variety of
functional groups on the ring, and has several advantages such
as one-pot operation, functional group tolerance, broad sub-
strate scope, and mild reaction conditions.
Scheme 3 Control experiments.
of 1a with 2a in the presence of 10 mol% In(OTf)3 in refluxing
toluene for 7 h afforded the desired cycloadduct 3a (26%) and
uncyclized product 6 (58%) (eqn (1), Scheme 3). The structure
of 6 was elucidated by spectral data analysis. Further reaction of
uncyclized 6 under standard conditions using Cu(OTf)2 as
the catalyst gave the desired product 3a in 87% yield. When
b-enamino ketone 2f was used instead of a b-enamino ester, the
cycloadduct was not formed, and compound 7 was produced in
75% yield (eqn (2), Scheme 3) In case of b-enamino ketone, the
enolate ion formed after Michael addition may be difficult to
attack to another b-enamino ketone due to its weaker Michael
acceptor ability compared to to b-enamino ester. In addition,
the reaction of aniline (1l), not containing nitrogen atoms in
the benzene ring, with 2a did not form annulation product 8, and
uncyclized adduct 9 was obtained in 21% yield. Interestingly, further
reaction of 9 under standard conditions gave no annulation product
8 (eqn (3), Scheme 3).
Based on the above results, the mechanism for the formation
of 3a is proposed in Scheme 4. In the first step, Michael addition
of 1a to complex 2a0, generated from 2a in the presence of a
Cu-catalyst, gives intermediate 10, which subsequently under-
goes further Michael addition to another molecule of 2a0 to form
intermediate 11. Elimination of two dimethylamine molecules
gives intermediate 6, which was isolated from the control
experiment. Isomerization of 6 in the presence of the Cu
Experimental
All reagents and solvents were purchased at the highest commercial
quality and used without further purification. All the reactions were
performed in oven-dried glassware with magnetic stirring. Merck,
pre-coated silica gel plates (Art. 5554) with a fluorescent indicator
were used for analytical TLC and were visualized with a UV lamp.
Flash column chromatography was performed using silica gel 9385
1
(Merck). H NMR spectra were recorded on Varian VNS or Bruker
DPX (600 or 300 MHz, respectively) spectrometers and the chemical
shifts were described in parts per million (d) relative to TMS (0 ppm)
as internal standard or relative to the resonance of the residual
protonated solvent (1H: CDCl3, d = 7.24 ppm). 13C NMR spectra were
obtained at 150 MHz or 75 MHz spectrometers and referenced to
the internal solvent signals (13C: CDCl3, d = 77.0 ppm). IR spectra
were recorded on a PerkinElmer Spectrum Twot IR spectrometer.
Melting points were measured with a Fisher Johns melting point
apparatus and uncorrected. The high-resolution mass spectra
(HRMS) were measured using a JEOL JMS-600 mass spectrometer
(positive ion EI mode) at the Korean Basic Science Institute.
General procedure for synthesis of compounds 3, 4 and 5
To a solution of heterocyclic amino compounds 1 (1.0 mmol)
and b-enamino esters 2 (2.0 eq.) in toluene (5.0 mL) was added
copper trifluoromethanesulfonate (10 mol%). The mixture was
stirred and refluxed for 10 h. After completion of reaction as
indicated by TLC, the reaction mixture was evaporated in rotary
evaporator and the residue was purified on a silica gel column
chromatography using hexane/ethyl acetate as eluent to afford
the desired product.
Characterization data of synthesized compounds 3, 4 and 5
Methyl 2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3a). Yield
72% (165 mg) as a white solid: m.p. 161–163 1C; 1H NMR
(600 MHz, CDCl3) d 8.71 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 4.2 Hz),
Scheme 4 Proposed reaction mechanism for the formation of 3a.
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7.90–7.87 (2H, m), 7.85–7.83 (1H, m), 7.35 (1H, t, J = 6.0 Hz), 6.60 1375, 1277, 1239, 1099, 1001, 844, 741 cmꢀ1; HRMS m/z (M+)
(1H, d, J = 10.2 Hz), 3.85 (3H, s); 13C NMR (150 MHz, CDCl3) d calcd for C19H16N2O4: 336.1110. Found: 336.1109.
164.6, 161.8, 151.0, 149.1, 141.6, 139.0, 137.9, 123.7, 121.2, 121.0,
Ethyl 40-(benzyloxy)-2-oxo-2H-[1,20-bipyridine]-5-carboxylate
110.3, 52.1; IR (neat) 3067, 1720, 1667, 1591, 1544, 1434, 1300, (3g). Yield 66% (230 mg) as a white solid: m.p. 129–131 1C;
1258, 1235, 1111, 967, 832, 763 cmꢀ1; HRMS m/z (M+) calcd for 1H NMR (600 MHz, CDCl3) d 8.21 (1H, d, J = 2.4 Hz), 8.16 (1H, d,
C12H10N2O3: 230.0691. Found: 230.0689.
J = 3.6 Hz), 7.90 (1H, dd, J = 9.6, 2.4 Hz), 7.38 (1H, d, J = 7.8 Hz),
Ethyl 2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3b). Yield 75% 7.35–7.32 (1H, m), 7.31–7.29 (4H, m), 7.27–7.25 (1H, m),
(184 mg) as a white solid: m.p. 120–122 1C; 1H NMR (600 MHz, 6.59 (1H, d, J = 9.6 Hz), 5.15 (1H, d, J = 12.0 Hz), 5.11 (1H, d,
CDCl3) d 8.69 (1H, d, J = 2.4 Hz), 8.60 (1H, s), 7.90 (1H, dd, J = 12.0 Hz) 4.27 (2H, q, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz); 13
C
J = 7.2, 2.4 Hz), 7.88–7.83 (2H, m), 7.36 (1H, t, J = 6.6 Hz), 6.60 NMR (150 MHz, CDCl3) d 164.1, 161.3, 149.8, 142.5 (*2C), 140.8,
(1H, d, J = 9.6 Hz), 4.31 (2H, q, J = 7.2 Hz) 1.33 (3H, t, 139.1, 135.4, 128.6, 128.1, 126.9, 125.7, 122.1, 120.2, 110.0, 70.9,
J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) d 164.1, 161.8, 151.1, 60.9, 14.2; IR (neat) 3067, 2825, 1666, 1438, 1375, 1277,
149.0, 141.5, 139.2, 137.9, 123.7, 121.4, 120.9, 110.7, 61.1, 14.3; 1239, 1099, 1001, 845, 771 cmꢀ1; HRMS m/z (M+) calcd for
IR (neat) 3067, 2994, 1679, 1543, 1436, 1303, 1270, 1108, 1017,
838, 765 cmꢀ1; HRMS m/z (M+) calcd for C13H12N2O3: 244.0848.
Found: 244.0849.
C
20H18N2O4: 350.1267. Found: 350.1267.
Methyl
40-methyl-2-oxo-2H-[1,20-bipyridine]-5-carboxylate
(3h). Yield 70% (172 mg) as a white solid: m.p. 156–158 1C;
3-Methylbut-2-en-1-yl 2-oxo-2H-[1,20-bipyridine]-5-carboxylate 1H NMR (600 MHz, CDCl3) d 8.65 (1H, s), 8.40 (1H, t, J = 4.8 Hz),
(3c). Yield 54% (154 mg) as a white solid: m.p. 111–113 1C; 7.88–7.85 (1H, m), 7.64 (1H, s), 7.15 (1H, s), 6.58 (1H, dd, J = 9.0,
1H NMR (600 MHz, CDCl3) d 8.68 (1H, s), 8.58 (1H, d, J = 4.8 Hz), 3.6 Hz) 3.83 (3H, s), 2.41 (3H, s); 13C NMR (150 MHz, CDCl3) d
7.90 (1H, dd, J = 10.2, 1.8 Hz), 7.89–7.82 (2H, m), 7.36–7.34 164.6, 161.8, 151.2, 149.6, 148.7, 141.8, 138.9, 124.8, 121.8,
(1H, m), 6.59 (1H, d, J = 10.2 Hz), 5.40–5.37 (1H, m), 4.75 (2H, d, 120.9, 110.2, 52.0, 21.1; IR (neat) 2961, 1722, 1677, 1545,
J = 7.8 Hz), 1.75 (3H, s), 1.72 (3H, s); 13C NMR (150 MHz, CDCl3) d 1436, 1265, 1100, 960, 836, 763 cmꢀ1; HRMS m/z (M+) calcd
164.2, 161.8, 151.1, 149.1, 141.5, 139.4, 139.2, 137.8, 123.7, 121.3, for C13H12N2O3: 244.0848. Found: 244.0845.
120.8, 118.3, 110.7, 61.9, 25.7, 18.0; IR (neat) 3051, 2978, 1672,
1543, 1434, 1298, 1254, 1103, 959, 835, 754 cmꢀ1; HRMS m/z (M+) Yield 76% (196 mg) as a white solid: m.p. 110–112 1C; 1H NMR
calcd for C16H16N2O3: 284.1161. Found: 284.1158. (600 MHz, CDCl3) d 8.60 (1H, d, J = 3.0 Hz), 8.39 (1H, d, J =
Ethyl 40-methyl-2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3i).
Benzyl 2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3d). Yield 65% 4.8 Hz), 7.86 (1H, dd, J = 10.2, 2.4 Hz), 7.61 (1H, s), 7.13 (1H, d,
(199 mg) as a white solid: m.p. 91–93 1C; 1H NMR (600 MHz, J = 4.8 Hz), 6.56 (1H, d, J = 10.2 Hz), 4.27 (2H, q, J = 7.2 Hz), 2.39
CDCl3) d 8.72 (1H, d, J = 2.4 Hz), 8.56 (1H, d, J = 4.8 Hz), 7.91 (3H, s), 1.29 (3H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) d
(1H, dd, J = 9.6, 2.4 Hz), 7.85–7.81 (2H, m), 7.39–7.30 (6H, m), 6.60 164.0, 161.8, 151.2, 149.5, 148.6, 141.6, 138.9, 124.8, 121.8,
(1H, d, J = 9.6 Hz), 5.30 (2H, s); 13C NMR (150 MHz, CDCl3) d 164.0, 120.7, 110.4, 60.9, 21.0, 14.2; IR (neat) 3108, 2996, 1725, 1675,
161.7, 151.0, 149.1, 141.8, 139.1, 137.8, 135.6, 128.5, 128.38, 128.32, 1542, 1295, 1253, 1167, 1105, 1028, 827, 761 cmꢀ1; HRMS m/z
123.7, 121.2, 120.9, 110.3, 66.7; IR (neat) 3061, 2924, 1677, 1544, (M+) calcd for C14H14N2O3: 258.1004. Found: 258.1006.
1437, 1298, 1254, 1103, 959, 835, 754 cmꢀ1; HRMS m/z (M+) calcd
for C18H14N2O3: 306.1004. Found: 306.1003.
3-Methylbut-2-en-1-yl 40-methyl-2-oxo-2H-[1,20-bipyridine]-5-
carboxylate (3j). Yield 61% (182 mg) as a white solid: m.p. 81–
Naphthalen-2-yl 2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3e). 83 1C; 1H NMR (600 MHz, CDCl3) d 8.62 (1H, d, J = 3.0 Hz), 8.39
Yield 49% (167 mg) as a white solid: m.p. 185–187 1C; 1H NMR (1H, d, J = 5.4 Hz), 7.89 (1H, dd, J = 9.6, 2.4 Hz), 7.63 (1H, s), 7.16
(600 MHz, CDCl3) d 8.98 (1H, d, J = 2.4 Hz), 8.61 (1H, d, (1H, d, J = 5.4 Hz), 6.59 (1H, d, J = 9.6 Hz), 5.39–5.36 (1H, m),
J = 4.2 Hz), 8.05 (1H, dd, J = 9.6, 2.4 Hz), 7.93 (1H, d, J = 4.74 (2H, d, J = 7.2 Hz), 2.42 (3H, s), 1.74 (3H, s), 1.72 (3H, s); 13
C
8.4 Hz), 7.89–7.84 (3H, m), 7.80 (1H, d, J = 7.8 Hz), 7.63 (1H, d, NMR (150 MHz, CDCl3) d 164.2, 161.9, 151.3, 149.7, 148.7,
J = 1.8 Hz), 7.50–7.45 (2H, m), 7.39–7.37 (1H, m), 7.30 (1H, dd, 141.7, 139.4, 139.1, 124.9, 121.9, 120.8, 118.4, 110.6, 61.9, 25.7,
J = 9.0, 2.4 Hz), 6.70 (1H, d, J = 9.6 Hz); 13C NMR (150 MHz, 21.1, 18.0; IR (neat) 2971, 1676, 1606, 1439, 1374, 1300, 1260,
CDCl3) d 163.0, 161.8, 151.0, 149.2, 148.1, 142.6, 139.1, 138.0, 1093, 839, 766 cmꢀ1; HRMS m/z (M+) calcd for C17H18N2O3:
133.7, 131.5, 129.5, 127.8, 127.6, 126.6, 125.8, 123.9, 121.3, 298.1317. Found: 298.1319.
121.2, 121.0, 118.6, 109.8; IR (neat) 3067, 2922, 2857, 1728,
Benzyl 40-methyl-2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3k).
1
1693, 1535, 1464, 1430, 1205, 1151, 1071, 750 cmꢀ1; HRMS m/z Yield 69% (221 mg) as a white solid: m.p. 119–121 1C; H NMR
(M+) calcd for C21H14N2O3: 342.1004. Found: 342.1002.
(600 MHz, CDCl3) d 8.66 (1H, d, J = 2.4 Hz), 8.40 (1H, d, J =
Methyl 40-(benzyloxy)-2-oxo-2H-[1,20-bipyridine]-5-carboxylate 5.4 Hz), 7.90 (1H, dd, J = 9.6, 1.8 Hz), 7.62 (1H, s), 7.38–7.31 (5H,
(3f). Yield 57% (193 mg) as a white solid: m.p. 127–129 1C; m), 7.15 (1H, d, J = 4.8 Hz), 6.59 (1H, d, J = 9.6 Hz), 5.29(2H, s),
1H NMR (600 MHz, CDCl3) d 8.21 (1H, d, J = 1.8 Hz), 8.16 (1H, 2.41 (3H, s); 13C NMR (150 MHz, CDCl3) d 164.0, 161.8, 151.2,
d, J = 4.8 Hz), 7.88 (1H, dd, J = 9.0, 1.8 Hz), 7.38 (1H, d, J = 8.4 Hz), 149.6, 148.7, 142.0, 139.0, 135.6, 128.5, 128.3, 128.3, 124.9, 121.8,
7.34–7.32 (1H, m), 7.31–7.29 (4H, m), 7.27–7.25 (1H, m), 6.58 (1H, 120.8, 110.1, 66.7, 21.1; IR (neat) 3025, 2969, 1723, 1680, 1544,
d, J = 9.0 Hz), 5.15 (1H, d, J = 12.0 Hz), 5.11 (1H, d, J = 12.0 Hz), 1437, 1370, 1258, 1091, 835, 759 cmꢀ1; HRMS m/z (M+) calcd for
3.80 (3H, s); 13C NMR (150 MHz, CDCl3) d 164.5, 161.2, 149.8, C19H16N2O3: 320.1161. Found: 320.1164.
142.7, 142.5, 140.8, 139.0, 135.4, 128.6, 128.1, 126.9, 125.7, 122.1,
120.3, 109.7, 70.9, 51.9; IR (neat) 3060, 2950, 1707, 1666, 1438, (3l). Yield 75% (194 mg) as a white solid: m.p. 150–152 1C;
Methyl 40-methoxy-2-oxo-2H-[1,20-bipyridine]-5-carboxylate
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1H NMR (300 MHz, CDCl3) d 8.71 (1H, d, J = 2.4 Hz), 8.37 (1H, d,
Ethyl 40-chloro-2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3r).
J = 5.7 Hz), 7.89 (1H, dd, J = 9.6, 2.7 Hz), 7.39 (1H, d, J = 2.1 Hz), Yield 59% (165 mg) as a white solid: m.p. 164–166 1C; 1H NMR
6.88 (1H, dd, J = 5.7, 2.1 Hz), 6.60 (1H, d, J = 9.6 Hz), 3.89 (3H, s), (600 MHz, CDCl3) d 8.69 (1H, d, J = 2.4 Hz), 8.47 (1H, d,
3.85 (3H, s); 13C NMR (75 MHz, CDCl3) d 167.0, 164.6, 161.8, J = 5.4 Hz), 7.97 (1H, s), 7.89 (1H, dd, J = 9.6, 2.4 Hz),
152.5, 149.7, 141.7, 139.0, 121.0, 110.9, 110.2, 106.8, 55.7, 52.1; 7.35 (1H, d, J = 4.8 Hz), 6.59 (1H, d, J = 9.6 Hz), 4.31 (2H, q,
IR (neat) 3088, 2956, 1724, 1677, 1547, 1436, 1312, 1267, 1098, J = 7.2 Hz), 1.33 (3H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) d
1026, 833, 763 cmꢀ1; HRMS m/z (M+) calcd for C13H12N2O4: 164.0, 161.6, 151.8, 149.4, 145.5, 141.0, 139.2, 124.1, 121.7,
260.0797. Found: 260.0796.
121.0, 110.9, 61.2, 14.2; IR (neat) 3094, 2989, 1720, 1677,
Methyl 40,60-dimethyl-2-oxo-2H-[1,20-bipyridine]-5-carboxylate 1545, 1393, 1307, 1267, 1107, 1018, 830, 766 cmꢀ1; HRMS m/z
(3m). Yield 76% (196 mg) as a white solid: m.p. 175–177 1C; (M+) calcd for C13H11ClN2O3: 278.0458. Found: 278.0459.
1H NMR (600 MHz, CDCl3) d 8.58 (1H, d, J = 2.4 Hz), 7.85 (1H, dd,
3-Methylbut-2-en-1-yl 40-chloro-2-oxo-2H-[1,20-bipyridine]-5-
J = 9.6, 2.4 Hz), 7.38 (1H, s), 7.01 (1H, s), 6.56 (1H, d, J = 9.6 Hz), carboxylate (3s). Yield 45% (145 mg) as a white solid: m.p.
3.83 (3H, s), 2.51 (3H, s), 2.36 (3H, s); 13C NMR (150 MHz, CDCl3) 124–126 1C; 1H NMR (600 MHz, CDCl3) d 8.69 (1H, d, J = 2.4 Hz),
d 164.7, 161.9, 158.3, 150.5, 149.7, 142.0, 138.8, 124.4, 120.8, 8.48 (1H, d, J = 4.8 Hz), 7.96 (1H, d, J = 1.2 Hz), 7.90 (1H, dd,
118.8, 110.0, 52.0, 23.9, 20.9; IR (neat) 2924, 1694, 1546, 1439, J = 10.2, 2.4 Hz), 7.36 (1H, dd, J = 5.4, 1.8 Hz), 6.60 (1H, d,
1365, 1276, 1217, 1103, 843, 765 cmꢀ1; HRMS m/z (M+) calcd for J = 10.2 Hz), 5.39 (1H, t, J = 7.2 Hz), 4.76 (2H, d, J = 7.8 Hz), 1.75
C14H14N2O3: 258.1004. Found: 258.1003.
(3H, s), 1.73 (3H, s); 13C NMR (150 MHz, CDCl3) d 164.1, 161.6,
Ethyl 40,60-dimethyl-2-oxo-2H-[1,20-bipyridine]-5-carboxylate 151.8, 149.5, 145.5, 141.0, 139.6, 139.3, 124.2, 121.7, 121.0,
(3n). Yield 72% (195 mg) as a white solid: m.p. 105–107 1C; 118.2, 111.0, 62.1, 25.7, 18.1; IR (neat) 3072, 2979, 1690, 1580,
1H NMR (600 MHz, CDCl3) d 8.56 (1H, d, J = 1.8 Hz), 7.87 1402, 1299, 1263, 1101, 956, 827, 766 cmꢀ1; HRMS m/z (M+)
(1H, dd, J = 10.2, 2.4 Hz), 7.37 (1H, s), 7.02 (1H, s), 6.57 (1H, d, calcd for C16H15ClN2O3: 318.0771. Found: 318.0774.
J = 9.6 Hz), 4.30 (2H, q, J = 7.2 Hz), 2.52 (3H, s), 2.36 (3H, s), 1.32
Benzyl 40-chloro-2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3t).
(3H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) d 164.2, 161.9, Yield 55% (188 mg) as a white solid: m.p. 105–107 1C; 1H NMR
158.3, 150.6, 149.7, 141.9, 138.9, 124.4, 120.7, 118.9, 110.3, 61.0, (600 MHz, CDCl3) d 8.73 (1H, s), 8.46 (1H, d, J = 5.4 Hz), 7.96
23.9, 20.9, 14.3; IR (neat) 2973, 1718, 1659, 1609, 1440, (1H, s), 7.91 (1H, dd, J = 9.6, 2.4 Hz), 7.39–7.31 (6H, m), 6.60 (1H,
1370, 1252, 1111, 857, 769 cmꢀ1; HRMS m/z (M+) calcd for d, J = 9.6 Hz), 5.30 (2H, s); 13C NMR (150 MHz, CDCl3) d 163.9,
C
15H16N2O3: 272.1161. Found: 272.1162.
161.5, 151.7, 149.5, 145.5, 141.3, 139.2, 135.5, 128.6, 128.4,
3-Methylbut-2-en-1-yl 40,60-dimethyl-2-oxo-2H-[1,20-bipyridine]- 128.3, 124.2, 121.7, 121.1, 110.6, 66.9; IR (neat) 3072, 2930,
5-carboxylate (3o). Yield 69% (215 mg) as a white solid: m.p. 1681, 1578, 1402, 1303, 1263, 1102, 831 cmꢀ1; HRMS m/z (M+)
82–84 1C; H NMR (300 MHz, CDCl3) d 8.54 (1H, d, J = 2.4 Hz), calcd for C18H13ClN2O3: 340.0615. Found: 340.0611.
1
7.86 (1H, dd, J = 9.6, 2.7 Hz), 7.34 (1H, s), 7.01 (1H, s), 6.55 (1H,
Methyl 6-oxo-1-(quinolin-2-yl)-1,6-dihydropyridine-3-carboxylate
d, J = 9.6 Hz), 5.36 (1H, t, J = 7.2 Hz), 4.72 (2H, d, J = 7.2 Hz), 2.50 (4a). Yield 73% (204 mg) as a white solid: m.p. 203–205 1C;
(3H, s), 2.34 (3H, s), 1.72 (3H, s), 1.70 (3H, s); 13C NMR (75 MHz, 1H NMR (600 MHz, CDCl3) d 8.83 (1H, s), 8.27 (1H, d, J = 9.0 Hz),
CDCl3) d 164.2, 161.9, 158.2, 150.5, 149.7, 141.9, 139.3, 139.0, 8.08 (1H, d, J = 9.0 Hz), 7.93 (1H, dd, J = 9.0, 1.2 Hz), 7.90–7.87
124.4, 120.6, 118.9, 118.3, 110.3, 61.8, 25.7, 23.9, 20.9, 18.0; IR (neat) (2H, m), 7.75 (1H, t, J = 7.2 Hz), 7.60 (1H, d, J = 7.2 Hz), 6.64 (1H,
2971, 1740, 1538, 1438, 1369, 1268, 1097, 941, 844, 767 cmꢀ1; HRMS d, J = 9.6 Hz), 3.87 (3H, s); 13C NMR (150 MHz, CDCl3) d 164.7,
m/z (M+) calcd for C18H20N2O3: 312.1474. Found: 312.1473.
162.1, 150.9, 147.0 141.9, 139.3, 137.9, 130.3, 129.0, 127.7, 127.58,
Benzyl 40,60-dimethyl-2-oxo-2H-[1,20-bipyridine]-5-carboxylate 127.54, 121.0, 118.9, 110.5, 52.1; IR (neat) 2986, 2897, 1725, 1672,
(3p). Yield 78% (261 mg) as a white solid: m.p. 136–138 1C; 1587, 1502, 1435, 1264, 1107, 1008, 832, 753 cmꢀ1; HRMS m/z (M+)
1H NMR (600 MHz, CDCl3) d 8.60 (1H, d, J = 1.8 Hz), 7.89 (1H, calcd for C16H12N2O3: 280.0848. Found: 280.0847.
dd, J = 9.6, 2.4 Hz), 7.38–7.30 (6H, m), 7.01 (1H, s), 6.57 (1H, d,
Ethyl 6-oxo-1-(quinolin-2-yl)-1,6-dihydropyridine-3-carboxylate
J = 9.6 Hz), 5.28 (2H, s), 2.50 (3H, s), 2.35 (3H, s); 13C NMR (4b). Yield 83% (244 mg) as a white solid: m.p. 135–137 1C;
(150 MHz, CDCl3) d 164.0, 161.8, 158.2, 150.4, 149.6, 142.1, 1H NMR (300 MHz, CDCl3) d 8.82 (1H, d, J = 2.4 Hz), 8.25 (1H, d,
138.8, 135.5, 128.4, 128.2, 128.1, 124.4, 120.6, 118.8, 109.9, 66.6, J = 8.7 Hz), 8.08 (1H, d, J = 8.4 Hz), 7.95–7.85 (3H, m), 7.74 (1H, t,
23.8, 20.9; IR (neat) 3029, 1739, 1612, 1547, 1439, 1368, 1273, J = 7.2 Hz), 7.60 (1H, t, J = 7.2 Hz), 6.62 (1H, d, J = 9.6 Hz), 4.33
1217, 1108, 846, 767 cmꢀ1; HRMS m/z (M+) calcd for C20H18N2O3: (2H, q, J = 7.2 Hz), 1.34 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz,
334.1317. Found: 334.1315.
CDCl3) d 164.2, 162.1, 151.0, 147.1, 141.7, 139.3, 137.9, 130.2,
Methyl 40-chloro-2-oxo-2H-[1,20-bipyridine]-5-carboxylate (3q). 129.1, 127.8, 127.5 (*2C), 121.0, 119.0, 110.9, 61.1, 14.3; IR (neat)
1
Yield 53% (141 mg) as a white solid: m.p. 184–186 1C; H NMR 2986, 2900, 1726, 1670, 1587, 1500, 1433, 1260, 1102, 1028, 827,
(600 MHz, CDCl3) d 8.73 (1H, d, J = 2.4 Hz), 8.47 (1H, d, 756 cmꢀ1; HRMS m/z (M+) calcd for C17H14N2O3: 294.1004.
J = 5.4 Hz), 7.99 (1H, s), 7.89 (1H, dd, J = 9.6, 2.4 Hz), 7.35 (1H, Found: 294.1006.
d, J = 5.4 Hz), 6.60 (1H, d, J = 9.6 Hz), 3.85 (3H, s); 13C NMR
3-Methylbut-2-en-1-yl 6-oxo-1-(quinolin-2-yl)-1,6-dihydropyridine-
(150 MHz, CDCl3) d 164.5, 161.5 151.7, 149.4, 145.5, 141.1, 139.1, 3-carboxylate (4c). Yield 68% (228 mg) as a white solid: m.p.
124.1, 121.6, 121.1, 110.6, 52.2; IR (neat) 3065, 2966, 1723, 1678, 139–141 1C; 1H NMR (600 MHz, CDCl3) d 8.80 (1H, s), 8.27
1579, 1433, 1404, 1304, 1257, 1110, 835, 761 cmꢀ1; HRMS m/z (1H, d, J = 9.0 Hz), 8.08 (1H, d, J = 9.0 Hz), 7.96–7.94 (1H, m),
(M+) calcd for C12H9ClN2O3: 264.0302. Found: 264.0303.
7.89–7.86 (2H, m), 7.76 (1H, t, J = 7.2 Hz), 7.61 (1H, t, J = 7.2 Hz),
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6.63 (1H, d, J = 9.0 Hz), 5.41–5.38 (1H, m), 4.77 (2H, d, J = 6.6 Hz), (3H, m), 7.71 (1H, t, J = 6.9 Hz), 7.62 (1H, t, J = 6.9 Hz), 7.37–7.29
1.74 (3H, s), 1.73 (3H, s); 13C NMR (150 MHz, CDCl3) d 164.2, (5H, m), 6.64 (1H, d, J = 9.6 Hz), 5.29 (2H, s); 13C NMR (75 MHz,
162.2, 150.9, 147.0, 141.8, 139.55, 139.52, 137.9, 130.3, 129.0, CDCl3) d 164.0, 161.8, 152.1, 145.1, 142.3, 138.7, 136.4, 135.5,
127.7, 127.58, 127.55, 120.9, 119.0, 118.3, 110.9, 62.0, 25.7, 18.0; 131.1, 128.4, 128.29, 128.24, 128.1, 128.0, 127.3, 127.2, 120.7,
IR (neat) 2969, 1722, 1672, 1591, 1500, 1385, 1261, 1113, 942, 117.5, 110.0, 66.6; IR (neat) 3032, 1718, 1677, 1544, 1442, 1301,
830, 755 cmꢀ1; HRMS m/z (M+) calcd for C20H18N2O3: 334.1317. 1259, 1105, 950, 834, 742 cmꢀ1; HRMS m/z (M+) calcd for
Found: 334.1315.
C
22H16N2O3: 356.1161. Found: 356.1163.
Benzyl 6-oxo-1-(quinolin-2-yl)-1,6-dihydropyridine-3-carboxylate
Methyl 6-oxo-1-(pyridazin-3-yl)-1,6-dihydropyridine-3-carboxylate
(4d). Yield 82% (293 mg) as a white solid: m.p. 169–171 1C; (5a). Yield 43% (99 mg) as a white solid: m.p. 192–194 1C;
1H NMR (600 MHz, CDCl3) d 8.85 (1H, d, J = 2.4 Hz), 8.25 (1H, d, 1H NMR (600 MHz, CDCl3) d 9.22 (1H, d, J = 4.8 Hz), 8.89 (1H, d,
J = 8.4 Hz), 8.06 (1H, d, J = 8.4 Hz), 7.96 (1H, dd, J = 10.2, 2.4 Hz), J = 2.4 Hz), 8.18 (1H, d, J = 9.0 Hz), 7.96 (1H, dd, J = 10.2, 2.4 Hz),
7.88–7.86 (2H, m), 7.74 (1H, t, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.64 (1H, dd, J = 9.0, 4.8 Hz), 6.63 (1H, d, J = 9.0 Hz), 3.86 (3H, s);
7.40 (2H, d, J = 6.6 Hz), 7.35 (2H, t, J = 7.2 Hz), 7.32 (1H, d, 13C NMR (150 MHz, CDCl3) d 164.3, 161.5, 155.5, 151.4, 141.0,
J = 7.2 Hz), 6.63 (1H, d, J = 10.2 Hz), 5.32 (2H, s); 13C NMR 140.0, 127.4, 125.5, 120.9, 111.1, 52.2; IR (neat) 3072, 2963, 1676,
(150 MHz, CDCl3) d 164.0, 162.0, 150.8, 147.0, 142.0, 139.3, 1435, 1273, 1101, 831, 761 cmꢀ1; HRMS m/z (M+) calcd for
137.9, 135.6, 130.2, 129.0, 128.5, 128.3, 128.2, 127.7, 127.5, C11H9N3O3: 231.0644. Found: 231.0646.
127.4, 121.0, 118.9, 110.5, 66.7; IR (neat) 2926, 1721, 1676,
1547, 1435, 1366, 1272, 1103, 832, 759 cmꢀ1; HRMS m/z (M+) (5b). Yield 54% (133 mg) as a white solid: m.p. 175–177 1C;
calcd for C22H16N2O3: 356.1161. Found: 356.1160.
1H NMR (300 MHz, CDCl3) d 9.22 (1H, d, J = 4.2 Hz), 8.87 (1H, d,
Ethyl 6-oxo-1-(pyridazin-3-yl)-1,6-dihydropyridine-3-carboxylate
Methyl 1-(isoquinolin-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate J = 2.4 Hz), 8.17 (1H, d, J = 8.7 Hz), 7.98 (1H, dd, J = 9.6, 2.4 Hz),
(4e). Yield 71% (198 mg) as a white solid: m.p. 183–185 1C; 7.65 (1H, dd, J = 8.7, 4.8 Hz), 6.64 (1H, d, J = 9.6 Hz), 4.33 (2H, q,
1H NMR (600 MHz, CDCl3) d 9.18 (1H, s), 8.78 (1H, s), 8.22 J = 7.2 Hz), 1.34 (3H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) d
(1H, s), 7.98 (1H, d, J = 8.4 Hz), 7.87–7.85 (2H, m), 7.70 (1H, t, 163.8, 161.5, 155.5, 151.4, 140.8, 140.1, 127.4, 125.6, 120.8,
J = 7.2 Hz), 7.61 (1H, t, J = 7.2 Hz), 6.61 (1H, d, J = 9.6 Hz), 3.81 111.4, 61.3, 14.2; IR (neat) 3095, 2993, 1723, 1678, 1433,
(3H, s); 13C NMR (150 MHz, CDCl3) d 164.7, 162.0, 152.1, 145.3, 1362, 1277, 1103, 831, 764 cmꢀ1; HRMS m/z (M+) calcd for
142.2, 138.7, 136.7, 131.2, 128.27, 128.22, 127.4, 127.3, 120.9,
117.5, 110.2, 52.0; IR (neat) 3052, 2966, 1716, 1680, 1613, 1544,
C
12H11N3O3: 245.0800. Found: 245.0803.
3-Methylbut-2-en-1-yl 6-oxo-1-(pyridazin-3-yl)-1,6-dihydro-
1447, 1302, 1267, 1101, 948, 837, 746 cmꢀ1; HRMS m/z (M+) pyridine-3-carboxylate (5c). Yield 32% (92 mg) as a brown solid:
calcd for C16H12N2O3: 280.0848. Found: 280.0845.
m.p. 80–82 1C; 1H NMR (600 MHz, CDCl3) d 9.22 (1H, d,
Ethyl 1-(isoquinolin-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate J = 4.8 Hz), 8.86 (1H, d, J = 2.4 Hz), 8.16 (1H, d, J = 7.8 Hz),
(4f). Yield 76% (225 mg) as a white solid: m.p. 126–128 1C; 7.97 (1H, dd, J = 9.6, 2.4 Hz), 7.64 (1H, dd, J = 9.0, 4.8 Hz), 6.63
1H NMR (600 MHz, CDCl3) d 9.20 (1H, s), 8.77 (1H, d, J = 2.4 Hz), (1H, d, J = 9.6 Hz), 5.38 (1H, t, J = 7.2 Hz), 4.76 (2H, d, J = 7.2 Hz),
8.22 (1H, s), 7.99 (1H, d, J = 7.8 Hz), 7.90 (1H, dd, J = 9.0, 2.4 Hz), 1.75 (3H, s), 1.73 (3H, s); 13C NMR (150 MHz, CDCl3) d 163.9,
7.87 (1H, d, J = 8.4 Hz), 7.71 (1H, t, J = 7.8 Hz), 7.62 (1H, t, 161.5, 155.5, 151.5, 140.9, 140.2, 139.8, 127.4, 125.5, 120.8,
J = 7.8 Hz), 6.63 (1H, d, J = 9.6 Hz), 4.30 (2H, q, J = 7.2 Hz), 1.31 118.1, 111.5, 62.1, 25.7, 18.0; IR (neat) 3085, 2927, 1705, 1674,
(3H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) d 164.1, 161.9, 1436, 1277, 1109, 931, 766 cmꢀ1; HRMS m/z (M+) calcd for
152.1, 145.3, 142.0, 138.7, 136.6, 131.1, 128.19, 128.13, 127.3,
127.2, 120.7, 117.5, 110.4, 60.9, 14.2; IR (neat) 3062, 2989, 1713,
C
15H15N3O3: 285.1113. Found: 285.1112.
Benzyl 6-oxo-1-(pyridazin-3-yl)-1,6-dihydropyridine-3-carboxylate
1668, 1543, 1443, 1389, 1292, 1243, 1167, 1100, 1014, 846, 750 (5d). Yield 37% (115 mg) as a brown semi solid: 1H NMR
419 cmꢀ1; HRMS m/z (M+) calcd for C17H14N2O3: 294.1004. (600 MHz, CDCl3) d 9.21 (1H, dd, J = 4.8, 1.5 Hz), 8.87 (1H, d,
Found: 294.1005.
J = 2.4 Hz), 8.14 (1H, dd, J = 8.7, 1.5 Hz), 7.99 (1H, dd, J = 9.6,
3-Methylbut-2-en-1-yl 1-(isoquinolin-3-yl)-6-oxo-1,6-dihydropyridine- 2.4 Hz), 7.63 (1H, dd, J = 8.7, 4.8 Hz), 7.37–7.36 (5H, m), 6.63
3-carboxylate (4g). Yield 67% (224 mg) as a white solid: m.p. (1H, d, J = 9.6 Hz), 5.30 (2H, s); 13C NMR (150 MHz, CDCl3) d
86–88 1C; 1H NMR (300 MHz, CDCl3) d 9.20 (1H, s), 8.77 (1H, d, 163.7, 161.5, 151.5, 141.1, 140.1, 135.4, 128.66, 128.61, 128.5,
J = 2.4 Hz), 8.22 (1H, s), 7.99 (1H, d, J = 8.1 Hz), 7.92–7.86 (2H, 128.4, 127.4, 125.5, 120.9, 111.1, 67.0; IR (neat) 3062, 2929,
m), 7.72 (1H, td, J = 6.9, 1.2 Hz), 7.62 (1H, td, J = 6.9, 1.2 Hz), 1720, 1674, 1432, 1275, 1099, 829, 746 cmꢀ1; HRMS m/z (M+)
6.63 (1H, d, J = 9.6 Hz), 5.40–5.35 (1H, m), 4.75 (2H, d, calcd for C17H13N3O3: 307.0957. Found: 307.0956.
J = 7.2 Hz), 1.73 (3H, s), 1.71 (3H, s); 13C NMR (75 MHz, CDCl3)
Methyl 6-oxo-1-(pyrazin-2-yl)-1,6-dihydropyridine-3-carboxylate
d 164.2, 162.0, 152.1, 145.4, 142.1, 139.3, 138.8, 136.6, 131.1, (5e). Yield 53% (123 mg) as white solid: m.p. 142–144 1C; 1H NMR
128.2, 128.1, 127.3, 127.2, 120.7, 118.3, 117.5, 110.5, 61.8, 25.6, (600 MHz, CDCl3) d 9.29 (1H, s), 8.70 (1H, d, J = 2.4 Hz), 8.62 (1H,
18.0; IR (neat) 2938, 1676, 1542, 1441, 1372, 1250, 1168, 1094, d, J = 1.8 Hz), 8.56 (1H, t, J = 1.8 Hz), 7.92 (1H, dd, J = 9.6, 2.4 Hz),
937, 837, 753 cmꢀ1; HRMS m/z (M+) calcd for C20H18N2O3: 6.63 (1H, d, J = 9.6 Hz), 3.86 (3H, s); 13C NMR (150 MHz, CDCl3) d
334.1317. Found: 334.1317.
164.3, 161.4, 147.6, 143.8, 143.1, 143.0, 140.6, 139.5, 121.1, 111.2,
Benzyl 1-(isoquinolin-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate 52.2; IR (neat) 3072, 2956, 1727, 1678, 1413, 1309, 1258, 1106,
(4h). Yield 80% (284 mg) as a white solid: m.p. 112–114 1C; 1H NMR 1014, 841, 763 cmꢀ1; HRMS m/z (M+) calcd for C11H9N3O3:
(300 MHz, CDCl3) d 9.18 (1H, s), 8.80 (1H, s), 8.20 (1H, s), 7.99–7.85 231.0644. Found: 231.0641.
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Ethyl 6-oxo-1-(pyrazin-2-yl)-1,6-dihydropyridine-3-carboxylate 143.5, 140.8, 138.4, 134.5, 130.5, 129.9, 125.9, 122.7, 118.7,
(5f). Yield 61% (149 mg) as white solid: m.p. 149–151 1C; 111.7, 94.8; IR (neat) 3070, 1627, 1542, 1474, 1429,
1H NMR (300 MHz, CDCl3) d 9.20 (1H, s), 8.68 (1H, d, 1270, 1222, 1146, 988, 742 cmꢀ1; HRMS m/z (M+) calcd for
J = 2.1 Hz), 8.62 (1H, s), 8.57 (1H, s), 7.92 (1H, dd, J = 9.6, 2.4 Hz),
6.63 (1H, d, J = 9.6 Hz), 4.32 (2H, q, J = 7.2 Hz), 1.33 (3H, t,
C
12H11N3O3: 302.0055. Found: 302.0056.
Dimethyl (2E,4E)-4-((phenylamino)methylene)pent-2-enedioate
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) d 163.8, 161.5, 143.7, (9). Yield 21% (55 mg) as a yellow solid: m.p. 116–118 1C; 1H NMR
143.1, 143.0, 140.5, 139.6, 137.6, 121.0, 111.5, 61.3, 14.2; IR (300 MHz, CDCl3) d 10.73 (1H, d, J = 12.9 Hz), 7.73 (1H, d,
(neat) 3095, 2995, 1715, 1657, 1472, 1398, 1250, 1131, 1012, 836, J = 13.2 Hz), 7.45 (1H, d, J = 15.6 Hz), 7.34 (2H, t, J = 7.5 Hz),
760 cmꢀ1; HRMS m/z (M+) calcd for C12H11N3O3: 245.0800. 7.05 (1H, d, J = 7.5 Hz), 7.05 (2H, d, J = 8.1 Hz), 6.16 (1H, d,
Found: 245.0797.
J = 15.9 Hz), 3.83 (3H, s), 3.73 (3H, s); 13C NMR (75 MHz, CDCl3)
Benzyl 6-oxo-1-(pyrazin-2-yl)-1,6-dihydropyridine-3-carboxylate d 169.3, 168.8, 148.0, 142.4, 139.2, 129.8, 124.5, 116.6, 110.6,
(5g). Yield 51% (158 mg) as a brown semi solid: 1H NMR 98.3, 51.3, 51.3; IR (neat) 3331, 2957, 1735, 1594, 1497, 1442,
(300 MHz, CDCl3) d 9.26 (1H, d, J = 1.2 Hz), 8.71 (1H, d, 1245, 1101, 756 cmꢀ1; HRMS m/z (M+) calcd for C12H11N3O3:
J = 2.4 Hz), 8.61 (1H, d, J = 2.4 Hz), 8.56–8.54 (1H, m), 7.94 261.1001. Found: 261.1004.
(1H, dd, J = 9.6, 2.4 Hz), 7.40–7.30 (5H, m), 6.63 (1H, d, J =
9.9 Hz), 5.31 (2H, s); 13C NMR (75 MHz, CDCl3) d 163.7, 161.4,
147.5, 143.8, 143.1, 142.9, 140.8, 139.5, 135.3, 128.5, 128.4,
Conflicts of interest
128.3, 121.0, 111.1, 66.9; IR (neat) 3064, 1714, 1672, 1407,
There are no conflicts to declare.
1299, 1237, 1099, 839, 746 cmꢀ1; HRMS m/z (M+) calcd for
C
17H13N3O3: 307.0957. Found: 307.0955.
Methyl 6-oxo-1-(pyrimidin-2-yl)-1,6-dihydropyridine-3-carboxylate Acknowledgements
(5h). Yield 58% (134 mg) as a white solid: m.p. 135–137 1C; 1H NMR
(300 MHz, CDCl3) d 8.90 (2H, d, J = 5.1 Hz), 8.49 (1H, d, J = 2.4 Hz),
7.89 (1H, dd, J = 9.6, 2.4 Hz), 7.42 (1H, t, J = 4.8 Hz), 6.64 (1H, d,
J = 9.6 Hz), 3.85 (3H, s); 13C NMR (75 MHz, CDCl3) d 164.4,
161.4, 159.2 (*2C), 158.7, 141.4, 139.0, 121.5, 120.9, 110.0, 52.1;
This work was supported by the 2016 Yeungnam University
Research Grant (216A061024).
Notes and references
IR (neat) 2923, 1685, 1571, 1405, 1254, 1108, 832, 763 cmꢀ1
;
HRMS m/z (M+) calcd for C11H9N3O3: 231.0644. Found:
231.0647.
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(5i). Yield 55% (135 mg) as a white solid: m.p. 146–148 1C;
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