Copper-Catalyzed N-O Cleavage of α,β-Unsaturated Ketoxime Acetates toward Structurally Diverse Pyridines

Article abstract of DOI:10.1021/acs.joc.9b03238

The copper-catalyzed [4 + 2] annulation of α,β-unsaturated ketoxime acetates with 1,3-dicarbonyl compounds for the synthesis of three classes of structurally diverse pyridines has been developed. This method employs 1,3-dicarbonyl compounds as C2 synthons and enables the synthesis of multifunctionalized pyridines with diverse electron-withdrawing groups in moderate to good yields. The mechanistic investigation suggests that the reactions proceed through an ionic pathway.

Full text of DOI:10.1021/acs.joc.9b03238

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Article
Copper-Catalyzed N-O Cleavage of #,#-Unsaturated
Ketoxime Acetates toward Structurally Diverse Pyridines
Lei Zhang, Jindian Duan, Gaochen Xu, Xiaojuan Ding, Yiyang Mao,
Binsen Rong, Ning Zhu, Zheng Fang, Zhenjiang Li, and Kai Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03238 • Publication Date (Web): 08 Jan 2020
Downloaded from pubs.acs.org on January 8, 2020
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Copper-Catalyzed N−O Cleavage of α,β-Unsaturated Ketoxime
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Acetates toward Structurally Diverse Pyridines
Lei Zhang,§ Jindian Duan,§ Gaochen Xu, Xiaojuan Ding, Yiyang Mao, Binsen Rong, Ning Zhu,
Zheng Fang, Zhenjiang Li, and Kai Guo*
College of Biotechnology and Pharmaceutical Engineering, State Key Laboratory of Materials-
Oriented Chemical Engineering, Nanjing Tech University, Nanjing 211816, China
ABSTRACT: The copper-catalyzed [4+2] annulation of α,β-unsaturated ketoxime acetates with
1,3-dicarbonyl compounds for the synthesis of three classes of structurally diverse pyridines has
been developed. This method employs 1,3-dicarbonyl compounds as C2 synthons and enables the
synthesis of multi-functionalized pyridines with diverse electron-withdrawing groups in moderate
to good yields. The mechanistic investigation suggests that the reactions proceed through an ionic
pathway.
KEYWORDS: Annulation, Copper, Ketoxime Acetates, 1,3-Dicarbonyl compounds, Pyridines
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INTRODUCTION
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Functionalized pyridines are the most abundant azaheteroaromatic structures that are embedded in
many natural products, functional materials, agrochemicals and pharmaceutical drugs.1 In
particular, they play pivotal roles in organic synthesis as building blocks and find use in catalysis
and coordination chemistry.2 Consequently, various synthetic methods, including transition-metal-
catalyzed reactions3 and the metal-free reactions,4 have been successfully established to access
these valuable substituted pyridines. Although some remarkable achievements have been made,
versatile and efficient methods for the direct construction of pyridines that are compatible with
various functional groups remain highly desirable. On the other hand, ketoximes and derivatives5
were used as meritorious building blocks for the synthesis and derivatization of pyridines6 as well
as many other nitrogen-containing heterocycles.7 Among them, transition metal-catalyzed
coupling reactions using α,β-unsaturated ketoximes as C3N1 synthons in structurally diverse
pyridine synthesis have gained increased attention. For example, Liebeskind and co-workers
developed Cu-catalyzed cross-coupling of vinyl ketoxime O-pentafluorobenzoates with
alkenylboronic acids in the modular construction of substituted pyridines (Scheme 1a).8 Hanzawa
et al. investigated the first Rh(I)-catalyzed intramolecular hetero-[4+2] cycloaddition of ω-
alkynyl-vinyl oximes for the synthesis of bicyclic pyridine compounds (Scheme 1b).9 Recent
advancements in transition metal-catalyzed annulation of α,β-unsaturated ketoximes with alkynes
or alkenes provided new routes for pyridine synthesis owing to the ability of the ketoxime
functionality to serve as a directing group for C−H activation, as has been reported by Cheng,10
Chiba,11 Ellman,12 Rovis,13 and others (Scheme 1c).14 Despite these advances, access to pyridines
with diverse electron-withdrawing groups have been rather limited. Nonetheless, the
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transformation of α,β-unsaturated ketoximes with other C2 reaction partners for the construction
of pyridines have never been documented.
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Scheme 1. The Annulation of α,β-Unsaturated Ketoximes for Pyridines Synthesis
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Inspired by the previous works,15 we envision that the nucleophilic iminylcopper(II) can be
generated through reduction of the α,β-unsaturated ketoxime acetate by copper, which adds to the
carbonyl group, followed by elimination and the subsequent processes to generate the substituted
pyridine. Herein, we disclose the copper-catalyzed coupling reactions of α,β-unsaturated ketoxime
acetates with various 1,3‐dicarbonyl compounds, delivering three classes of structurally diverse
pyridines that are difficult to assemble through traditional condensation approaches (Scheme 1d).
RESULTS AND DISCUSSION
Initially, we employed ketoxime-enoate 1a and acetylacetone 2a as benchmark substrates to
explore the optimal reaction conditions. To our delight, the desired product 3aa was isolated in
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83% yield by using CuI as the catalyst in DCE at 120 °C for 12 h under N2 atmosphere (Table 1,
entry 1). A brief survey of various solvents demonstrated that THF was the most ideal, affording
the product 3aa in 93% yield (entry 4), as the reaction became sluggish in other solvents such as
MeCN and toluene (entry 2−3). In addition, other copper catalysts also effectively produced the
desired product in reasonable yields (entry 5−9). No further improvement of the yield was obtained
by screening of various additives (entry 10−12). Finally, either increasing or decreasing the
reaction temperature resulted in lower yields of 3aa (entries 13−14). To demonstrate the possibility
of large-scale operation, scale up experiments were conducted at the 10 mmol scale to synthesize
3aa in 88% yield (entry 15).
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Table 1. Optimization of Reaction Conditionsa
entry [Cu]
solvent additive yield (%)
1
2
3
CuI
CuI
CuI
DCE
MeCN None
toluene None
None
83
81
69
93
75
72
86
83
79
72
87
4
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7
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13b
14c
15d
CuI
THF
THF
THF
THF
THF
None
None
None
None
None
None
KOAc
Li2CO3
CuCl
CuBr
CuCN
CuCl2
Cu(OAc)2 THF
CuI
CuI
CuI
CuI
CuI
CuI
THF
THF
THF
THF
THF
THF
NaHSO3 70
None
None
None
90
89
88
aReaction conditions: oxime 1a (0.4 mmol),
acetylacetone 2a (0.2 mmol), copper salt (20 mol%),
and additive (2 equiv) in solvent (2 mL) at 120 °C for
b
c
d
12 h under N2. Isolated yields. 110˚C. 130˚C. 10
mmol scale.
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With the optimal reaction conditions established, we then investigated the versatility and
limitations of the current copper-catalyzed synthesis of multi-functionalized pyridines, and the
representative examples were summarized in Scheme 2. First, various substituted ketoxime-
enoates 1, regardless of the electronic properties, steric hindrances, and substitution positions on
the aromatic ring, were broadly tolerated and reacted smoothly with acetylacetone 2a to generate
the corresponding products 3aa−3ka in moderate to good yields (60−93%). Other ketoxime-
enoates 1 with aromatic rings such as biphenyl, β-naphthyl and thiophenyl were also tested in this
transformation, and they all demonstrated good reaction efficiency (3la−3na). Also tert-butyl
substituted ketoxime-enoate readily participated in this reaction, giving rise to 3oa in 67% yield.
However, the methyl-substituted counterparts failed to generate the desired product. Subsequently,
we tested the protocol with a set of 1,3-dicarbonyl compounds. β-Diketones such as 3,5-
heptanedione and benzoylacetone could also be employed to deliver the desired pyridine
derivatives 3ab and 3ac in 54% and 65% yields, respectively. Ethyl, tbutyl, and allyl acetoacetates
were also suitable substrates, providing the desired products in moderate to good yields. Notably,
CF3-substituted β-diketones and ketoxime-enoates showed similar reactivity under the standard
conditions, furnishing the targeted products in good yields (3ag−3mi). The structure of 3ai was
unambiguously confirmed by single-crystal X-ray analysis. Therefore, this protocol provides
viable access to a diverse range of 2-CF3 substituted pyridines. Moreover, cyclic β-diketones were
all efficient for the present transformation and the corresponding bicyclic products 3aj−3am were
afforded without any difficulties. When dibenzoylmethane was employed, the desired product 3an
was isolated in 42% yield along with the unexpected product 3an' in 30% yield, which might be
attributed to the debenzoylation of 3an assisted by Cu(I) salt in the prensence of water. However,
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no desired products were obtained when the unactivated aryl/alkyl ketones such as phenylpropone
and 2-pentanone were used as substrates in the current protocol.
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Scheme 2. Reactions of Various Ketoxime-enoates with 1,3-Dicarbonyl Compoundsa
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aReaction conditions: 1 (0.4 mmol), 2 (0.2 mmol) and CuI (20 mol%) in THF (2 mL) at 120 °C
for 12 h under N2. Isolated yields.
The above satisfying results prompted us to further investigate the scope of the transformation.
However, when we utilized hexafluoroacetylacetone 4 as the coupling partner, the 2,4,6-
trisubstituted pyridine 5a was obtained in 85% yield. To evaluate the generality of this process,
various ketoxime-enoates 1 were subjected to the reaction with hexafluoroacetylacetone 4. As
shown in Scheme 3, various substituents bearing electron-donating groups (Me, MeO) or electron-
withdrawing groups (F, Cl, Br, CN, NO2) on the aromatic ring of the ketoxime-enoate were well-
tolerated, leading to the formation of desired pyridines 5b−j in moderate to good yields. The results
indicated that no significant electronic effects or steric hindrances were observed. Biphenyl, β-
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naphthyl and thiophenyl-substituted ketoxime-enoate also proceeded smoothly as well to give the
corresponding products (5k−m).
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Scheme 3. Reactions of Various Ketoxime-enoates with Hexafluoroacetylacetonea
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aReaction conditions: 1 (0.4 mmol), 4 (0.2 mmol) and CuI (20 mol%) in THF (2 mL) at 120 °C
for 12 h under N2. Isolated yields.
When ketoxime-enoates 1 and acetoacetanilide 6 were conducted under the stand conditions,
the bicyclic fused pyridines were synthesized instead of the previous products. Various ketoxime-
enoates 1 exhibited good functional-group tolerance, irrespective of the position and electronic
property of substituents on the phenyl moiety, and all performed well for the transformation to
deliver the desired bicyclic products in high to excellent yield (Scheme 4). In addition, biphenyl,
β-naphthyl, thiophenyl and alkyl (tBu, Me) substituted ketoxime-enoates were also applicable in
this transformation, providing access to functionalized pyridines 7l−p in 32−66% yields,
respectively.
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Scheme 4. Reactions of Various Ketoxime-enoates with Acetoacetanilidea
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aReaction conditions: 1 (0.4 mmol), 6 (0.2 mmol) and CuI (20 mol%) in THF (2 mL) at 120 °C
for 12 h under N2. Isolated yields.
To further develop the scope of this reaction, other types of ketoxime acetates were also
examined in the [4+2] annulation protocol (Scheme 5). Chalcone, benzalacetone and 1-phenylhex-
2-en-1-one derived oxime acetates were all amenable substrates, furnishing the desired pyridines
with the coupling of acetylacetone 2a or acetoacetanilide 6 in moderate yields. However,
hexafluoroacetylacetone 4 was inefficient coupling partner under the standard conditions (not
shown).
Scheme 5. Reactions of Ketoxime Acetates with 2a or 6a
aReaction conditions: 1 (0.4 mmol), 2a or 6 (0.2 mmol) and CuI (20 mol%) in THF (2 mL) at
120 °C for 12 h under N2. Isolated yields.
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To gain more insight into the reaction mechanism, the radical scavenger TEMPO or BHT was
added to the reaction system, while pyridine 3a was still obtained without obvious inhibition or
sluggishness (Scheme 6), and no radical capture intermediate was detected, thus indicating an ionic
pathway instead of the radical process.
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Scheme 6. Mechanistic Studies
Based on the experimental results and previous studies, the tentative mechanism is postulated
in Scheme 7 to account for the construction of diverse pyridines. Oxidation of Cu(I) salt by
ketoxime-enoate 1a through cleavage of the N−O bond generates iminylcopper(II) intermediate A
together with a Cu(II) species. Subsequently, nucleophilic addition of A to the carbonyl of 1,3-
diketone gives intermediate B followed by β-elimination to afford the aza-hexa-1,3,5-triene
intermediate C. Then the intermediate C undergoes thermal 6π-electrocyclization and rapid
oxidation by the Cu(II) species16a to furnish the pyridine derivatives D, E and F, while regenerating
the copper(I) catalyst for catalytic cycle. Additionally, an alternative approach might still be valid
for the pyridines synthesis. The iminylcopper(II) intermediate A deprotonates 1,3-diketone to
generate α,β-unsaturated imine and stabilizes copper enolate of 1,3-diketone. Next, the copper
enolate undergoes Michael addition to unsaturated imine, followed by intramolecular N-
nucleophilic attack of the carbonyl of 1,3-diketone to generate intermediate B′. Subsequent
elimination of Cu(II) hydroxide and oxidation by the Cu(II) species would furnish the pyridine
derivatives.6f-h Finally, deacetylation of the pyridine E assisted by Cu(I) salt17 in the prensence of
water formed the 2-CF3 substituted pyridine 5a and polycyclic pyridine 7a was obtained through
amidation cyclization of the pyridine F.
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Scheme 7. Proposed Mechanism of the Copper-Catalyzed Pyridines Synthesis
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In summary, we have developed the copper-catalyzed formal [4+2] annulation of α,β-
unsaturated ketoxime acetates with 1,3‐dicarbonyl compounds, providing access to monocyclic
and bicyclic fused pyridines with diverse electron-withdrawing groups in generally moderate to
good yields. This protocol features operational simplicity, high efficiency and functional group
compatibility, representing an alternate route towards the synthesis of pyridine derivatives. Further
investigations involving the application of this methodology and novel pyridines design are
ongoing in our laboratory.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all experiments were performed under argon
atmosphere. Commercial solvents and reagents were used without further purification. Thin-layer
chromatography (TLC) was performed on silica gel plates (60F-254) using UV-light (254 nm).
Flash chromatography was conducted on silica gel (200-300 mesh). NMR (400 MHz for 1H NMR,
101 MHz for 13C NMR) spectra were recorded in CDCl3 with TMS as the internal standard.
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Chemical shifts are reported in ppm and coupling constants are given in Hz. Data for 1H NMR are
recorded as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quarter;
m, multiplet), coupling constant (Hz), integration. Data for 13C NMR are reported in terms of
chemical shift (δ, ppm). High-resolution mass spectra (HRMS) were obtained on an Agilent mass
spectrometer using ESI-TOF (electrospray ionization-time of flight). Ketoxime acetates 1a,15
1q,11a 1b–1p16 and 1r–1s16 were prepared according to the related literatures (see the Supporting
Information for details).
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General Procedure for Synthesis of Polysubstituted Pyridine Derivatives. Ketoxime acetates (0.4
mmol, 2.0 equiv), 1,3‐dicarbonyl compounds (0.2 mmol, 1.0 equiv) and CuI (7.6 mg, 0.04 mmol)
were loaded into a Schlenk tube equipped with a Teflon-coated magnetic stir bar. The Schlenk
tube was placed under vacuum for 1 min and then N2 was pumped into it. The solvent THF (2 mL,
0.1 M) was added into the Schlenk tube by syringe. The tube was sealed and magnetically stirred
in a preheated 120 °C oil bath for 12 h (Caution! The protection shield was needed). Then the
reaction tube was allowed to cool to room temperature and the reaction solution was concentrated
under reduced pressure. The crude products were purified by column chromatography on silica gel
(Petroleum Ether/EtOAc) to give the pyridine derivatives.
Ethyl 3-Acetyl-2-methyl-6-phenylisonicotinate (3aa). White solid; 53 mg, 93% yield; mp
76−78 °C ; Rf = 0.2 (petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, Chloroform-d): δ
8.08 (s, 1H), 8.04 (dd, J = 8.1, 1.3 Hz, 2H), 7.53–7.44 (m, 3H), 4.41 (q, J = 7.1 Hz, 2H), 2.61 (s,
3H), 2.60 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 204.7,
165.0, 157.7, 154.1, 138.1, 135.5, 135.3, 129.7, 128.9, 127.1, 117.3, 62.4, 31.8, 22.6, 14.1 ppm;
HRMS (ESI-TOF): m/z calcd for C17H18NO3 [M+H]+ 284.1281, found 284.1294.
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Ethyl 3-Acetyl-6-(4-fluorophenyl)-2-methylisonicotinate (3ba). Yellow solid; 45 mg, 75% yield;
5
6
1
mp 80−83 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 10:1); H NMR (400 MHz, Chloroform-
7
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d): δ 8.07–7.99 (m, 3H), 7.15 (t, J = 8.7 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.58 (s, 6H), 1.40 (t, J
= 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 204.5, 165.1 (d, J = 250.6 Hz),
164.9, 156.5, 154.2, 135.4, 134.2 (d, J = 3.2 Hz), 129.0 (d, J = 8.5 Hz), 116.8, 115.9 (d, J = 21.8
Hz), 62.5, 31.8, 22.5, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for C17H17NO3F [M+H]+ 302.1187,
found 302.1203.
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Ethyl 3-Acetyl-6-(4-chlorophenyl)-2-methylisonicotinate (3ca). White solid; 58 mg, 91% yield;
1
mp 73−74 °C ; Rf = 0.3 (petroleum ether/ethyl acetate = 10:1); H NMR (400 MHz, Chloroform-
d): δ 8.04 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.60
13
(s, 3H), 2.59 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ
204.4, 164.8, 156.3, 154.3, 136.4, 135.9, 135.7, 135.5, 129.1, 128.3, 62.5, 31.8, 22.6, 14.0 ppm;
HRMS (ESI-TOF): m/z calcd for C17H17NO3Cl [M+H]+ 318.0891, found 318.0917.
Ethyl 3-Acetyl-6-(4-cyanophenyl)-2-methylisonicotinate (3da). White solid; 37 mg, 60% yield;
Rf = 0.2 (petroleum ether/ethyl acetate = 5:1); mp 124−125 °C; 1H NMR (400 MHz, Chloroform-
d): δ 8.17 (d, J = 8.4 Hz, 2H), 8.11 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.60
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(s, 3H), 2.59 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ
204.0, 164.5, 155.2, 154.8, 142.0, 136.7, 135.6, 132.7, 127.6, 118.6, 117.7, 113.1, 62.7, 31.7, 22.6,
14.0 ppm; HRMS (ESI-TOF): m/z calcd for C18H17N2O3 [M+H]+ 309.1234, found 309.1249.
Ethyl 3-Acetyl-2-methyl-6-(4-nitrophenyl)isonicotinate (3ea). Light yellow solid; 43 mg, 66%
1
yield; Rf = 0.2 (petroleum ether/ethyl acetate = 5:1); mp 127−128 °C; H NMR (400 MHz,
Chloroform-d): δ 8.34 (d, J = 8.9 Hz, 2H), 8.24 (d, J = 9.0 Hz, 2H), 8.15 (s, 1H), 4.43 (q, J = 7.1
Hz, 2H), 2.63 (s, 3H), 2.60 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
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Chloroform-d): δ 203.9, 164.5, 154.9, 154.8, 148.6, 143.7, 136.9, 135.7, 127.9, 124.1, 117.9, 62.7,
31.7, 22.5, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for C17H17N2O5 [M+H]+ 329.1132, found
329.1151.
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Ethyl 3-Acetyl-2-methyl-6-(p-tolyl)isonicotinate (3fa). Light yellow solid; 51 mg, 85% yield; Rf
= 0.2 (petroleum ether/ethyl acetate = 5:1); mp 66–67 °C; 1H NMR (400 MHz, Chloroform-d): δ
8.04 (s, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.59 (s,
3H), 2.58 (s, 3H), 2.41 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
Chloroform-d): δ 204.7, 165.1, 157.6, 154.0, 139.8, 135.3, 135.1, 129.6, 126.9, 116.9, 62.4, 31.8,
22.6, 21.4, 14.1 ppm; HRMS (ESI-TOF): m/z calcd for C18H20NO3 [M+H]+ 298.1438, found
298.1452.
Ethyl 3-Acetyl-6-(4-methoxyphenyl)-2-methylisonicotinate (3ga). Light yellow solid; 58 mg, 93%
1
yield; Rf = 0.2 (petroleum ether/ethyl acetate = 8:1); mp 93–95 °C ; H NMR (400 MHz,
Chloroform-d): δ 8.03–7.98 (m, 3H), 6.99 (d, J = 8.9 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.86 (s,
3H), 2.57 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 204.8,
165.1, 161.0, 157.2, 153.9, 135.3, 134.7, 130.6, 128.4, 116.4, 114.2, 62.3, 55.4, 31.8, 22.6, 14.0
ppm; HRMS (ESI-TOF): m/z calcd for C18H20NO4 [M+H]+ 314.1387, found 314.1409.
Ethyl 3-Acetyl-6-(3-bromophenyl)-2-methylisonicotinate (3ha). Yellow oil; 51 mg, 70% yield; Rf
= 0.4 (petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, Chloroform-d): δ 8.14 (s, 1H),
7.96 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.52–7.46 (m, 1H), 7.27 (t, J = 7.9 Hz, 1H), 4.34 (q, J = 7.1
Hz, 2H), 2.52 (s, 3H), 2.51 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
Chloroform-d): δ 204.3, 164.7, 155.9, 154.4, 140.0, 136.1, 135.5, 132.5, 130.4, 130.1, 125.6, 123.2,
117.2, 62.5, 31.7, 22.5, 14.1 ppm; HRMS (ESI, ESI-TOF): m/z calcd for C17H17NO3Br [M+H]+
362.0386, found 362.0403.
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Ethyl 3-Acetyl-6-(3-methoxyphenyl)-2-methylisonicotinate (3ia). White solid; 38 mg, 60% yield;
Rf = 0.3 (petroleum ether/ethyl acetate = 10:1); mp 106–107 °C ; 1H NMR (400 MHz, Chloroform-
d): δ 8.06 (s, 1H), 7.63–7.56 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 6.99 (dd, J = 8.9, 2.5 Hz, 1H), 4.40
(q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.60 (s, 3H), 2.59 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}
NMR (101 MHz, Chloroform-d): δ 204.6, 165.0, 160.1, 157.4, 154.1, 139.5, 135.6, 135.3, 129.9,
119.5, 117.4, 115.4, 112.5, 62.4, 55.4, 31.8, 22.6, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for
C18H20NO4 [M+H]+ 314.1387, found 314.1408.
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Ethyl 3-Acetyl-6-(2-fluorophenyl)-2-methylisonicotinate (3ja). White solid; 43 mg, 72% yield; Rf
= 0.4 (petroleum ether/ethyl acetate = 10:1); mp 89–90 °C; 1H NMR (400 MHz, Chloroform-d): δ
8.15 (s, 1H), 7.99 (td, J = 7.8, 1.6 Hz, 1H), 7.42 (ddd, J = 13.3, 6.2, 1.6 Hz, 1H), 7.29 (d, J = 7.5
Hz, 1H), 7.22–7.16 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.61 (s, 3H), 1.40 (t, J = 7.1
Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 204.4, 164.9, 161.8 (d, J = 251.4 Hz),
154.1, 153.6 (d, J = 2.1 Hz), 135.9, 135.0, 131.2 (d, J = 8.6 Hz), 131.0 (d, J = 2.5 Hz), 126.3 (d, J
= 11.4 Hz), 124.7 (d, J = 3.6 Hz), 121.3 (d, J = 9.8 Hz), 116.4 (d, J = 22. 8 Hz), 62.4, 31.8, 22.5,
14.0 ppm; HRMS (ESI-TOF): m/z calcd for C17H17NO3F [M+H]+ 302.1187, found 302.1203.
Ethyl 3-Acetyl-6-(2-methoxyphenyl)-2-methylisonicotinate (3ka). White solid; 54 mg, 86% yield;
Rf = 0.3 (petroleum ether/ethyl acetate = 10:1); mp 100–102 °C; 1H NMR (400 MHz, Chloroform-
d): δ 8.18 (s, 1H), 7.77 (dd, J = 7.6, 1.7 Hz, 1H), 7.38 (td, J = 8.3, 1.8 Hz, 1H), 7.12–6.94 (m, 2H),
4.38 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.58 (s, 3H), 2.58 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, Chloroform-d): δ 204.8, 165.2, 157.1, 156.4, 153.5, 135.0, 134.3, 131.1,
130.6, 127.8, 122.0, 121.2, 111.5, 62.2, 55.7, 31.8, 22.5, 14.0 ppm; HRMS (ESI-TOF): m/z calcd
for C18H20NO4 [M+H]+ 314.1387, found 314.1407.
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Ethyl 6-([1,1'-Biphenyl]-4-yl)-3-acetyl-2-methylisonicotinate (3la). White solid; 63 mg, 88%
yield; Rf = 0.2 (petroleum ether/ethyl acetate = 10:1); mp 115–116 °C; 1H NMR (400 MHz,
Chloroform-d): δ 8.15 (s, 1H), 8.13 (s, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 7.47
(t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 2.61 (s, 3H),
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1.42 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 204.6, 165.0, 157.1,
154.2, 142.4, 140.4, 136.9, 135.5, 135.4, 128.9, 127.7, 127.6, 127.5, 127.1, 117.1, 62.4, 31.8, 22.6,
14.1 ppm; HRMS (ESI, ESI-TOF): m/zcalcd for C23H22NO3 [M+H]+ 360.1594, found 360.1583.
Ethyl 3-Acetyl-2-methyl-6-(naphthalen-2-yl)isonicotinate (3ma). White solid; 53 mg, 80% yield;
Rf = 0.2 (petroleum ether/ethyl acetate = 10:1); mp 130–132 °C; 1H NMR (400 MHz, Chloroform-
d): δ 8.53 (s, 1H), 8.23–8.14 (m, 2H), 7.96 (t, J = 8.4 Hz, 2H), 7.87 (dd, J = 5.9, 3.3 Hz, 1H), 7.52
(dd, J = 6.2, 3.2 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H), 2.63 (d, J = 15.3 Hz, 6H), 1.43 (t, J = 7.1 Hz,
3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 204.5, 165.0, 157.4, 154.2, 135.5, 135.4,
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135.3, 134.0, 133.4, 128.8, 128.6, 127.7, 126.9, 126.8, 126.5, 124.4, 117.4, 62.5, 31.8, 22.6, 14.1
ppm; HRMS (ESI-TOF): m/z calcd for C21H20NO3 [M+H]+ 334.1438, found 334.1462.
Ethyl 3-Acetyl-2-methyl-6-(thiophen-2-yl)isonicotinate (3na). Yellow solid; 45 mg, 78% yield;
Rf = 0.2 (petroleum ether/ethyl acetate = 10:1); mp 83–84 °C; 1H NMR (400 MHz, Chloroform-
d): δ 7.94 (s, 1H), 7.66 (d, J = 3.7 Hz, 1H), 7.43 (d, J = 5.0 Hz, 1H), 7.14–7.09 (m, 1H), 4.39 (q, J
= 7.1 Hz, 2H), 2.55 (s, 3H), 2.53 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
Chloroform-d) δ 204.3, 164.8, 154.2, 152.8, 143.5, 135.3, 135.1, 128.7, 128.2, 125.7, 115.6, 62.5,
31.8, 22.4, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for C15H16NO3S [M+H]+ 290.0845, found
290.0848.
Ethyl 3-Acetyl-6-(tert-butyl)-2-methylisonicotinate (3oa). Yellow oil; 35 mg, 67% yield; Rf = 0.4
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(q, J = 7.1 Hz, 2H), 2.53 (s, 3H), 2.48 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H) ppm; 13C{1H}
NMR (101 MHz, Chloroform-d): δ 205.2, 169.9, 165.4, 152.7, 134.6, 134.3, 115.6, 62.2, 37.6,
31.7, 29.9, 22.5, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for C15H22NO3 [M+H]+ 264.1594, found
264.1595.
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Ethyl 2-Ethyl-6-phenyl-3-propionylisonicotinate (3ab). Yellow oil; 34 mg, 54% yield; Rf = 0.3
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, Chloroform-d): δ 8.15–8.03 (m, 3H),
7.47 (dt, J = 13.9, 7.0 Hz, 3H), 4.39 (q, J = 7.1 Hz, 2H), 2.86–2.73 (m, 4H), 1.38 (td, J = 7.3, 6.2
Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 207.4, 165.0,
159.1, 157.5, 138.2, 135.5, 134.9, 129.6, 128.8, 127.0, 117.1, 62.3, 38.1, 29.0, 14.1, 13.8, 7.8 ppm;
HRMS (ESI-TOF): m/z calcd for C19H22NO3 [M+H]+ 312.1594, found 312.1599.
Ethyl 3-Benzoyl-2-methyl-6-phenylisonicotinate (3ac). White solid; 45 mg, 65% yield; Rf = 0.3
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(petroleum ether/ethyl acetate = 10:1); mp 113–114 C; H NMR (400 MHz, Chloroform-d): δ
8.19 (s, 1H), 8.11 (dd, J = 8.2, 1.3 Hz, 2H), 7.82 (d, J = 7.2 Hz, 2H), 7.63–7.57 (m, 1H), 7.55–7.44
(m, 5H), 4.17 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, Chloroform-d): δ 196.7, 164.8, 157.9, 156.1, 138.1, 137.2, 137.0, 133.6, 132.7, 129.7, 129.0,
128.9, 128.9, 127.1, 117.4, 62.2, 23.1, 13.6 ppm; HRMS (ESI-TOF): m/z calcd for C22H20NO3
[M+H]+ 346.1438, found 346.1456.
Diethyl 2-Methyl-6-phenylpyridine-3,4-dicarboxylate (3ad). White solid; 40 mg, 64% yield; Rf =
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0.4 (petroleum ether/ethyl acetate = 10:1); mp 66–68 C; H NMR (400 MHz, Chloroform-d): δ
7.96 (dd, J = 9.0, 2.3 Hz, 3H), 7.44–7.34 (m, 3H), 4.40–4.29 (m, 4H), 2.61 (s, 3H), 1.32 (td, J =
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7.2, 3.5 Hz, 6H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 168.3, 165.1, 158.1, 156.3,
138.1, 137.2, 129.7, 128.9, 127.2, 126.7, 117.0, 62.2, 61.9, 22.9, 14.1, 14.1 ppm; HRMS (ESI-
TOF): m/z calcd for C18H20NO4 [M+H]+ 314.1387, found 314.1383.
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3-(Tert-butyl) 4-Ethyl 2-methyl-6-phenylpyridine-3,4-dicarboxylate (3ae). White solid; 40 mg,
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58% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); mp 93–95 C; H NMR (400 MHz,
Chloroform-d): δ 8.02 (dd, J = 8.2, 1.4 Hz, 2H), 7.98 (s, 1H), 7.51–7.41 (m, 3H), 4.43 (q, J = 7.1
Hz, 2H), 2.72 (s, 3H), 1.64 (s, 9H), 1.41 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
Chloroform-d): δ 167.1, 165.2, 157.6, 156.2, 138.2, 137.0, 129.6, 128.8, 127.8, 127.1, 117.0, 82.9,
62.1, 28.0, 22.9, 14.2 ppm; HRMS (ESI-TOF): m/z calcd for C20H24NO4 [M+H]+ 342.1700, found
342.1703.
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3-Allyl 4-Ethyl 2-methyl-6-phenylpyridine-3,4-dicarboxylate (3af). Yellow oil; 32 mg, 49% yield;
Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, Chloroform-d): δ 8.10–7.98
(m, 3H), 7.48 (d, J = 7.4 Hz, 3H), 6.05 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.44 (dq, J = 17.2, 1.5 Hz,
1H), 5.32 (dq, J = 10.5, 1.3 Hz, 1H), 4.93–4.84 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H),
1.39 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 167.9, 165.0, 158.2,
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156.4, 138.0, 137.4, 131.6, 129.8, 128.9, 127.2, 126.3, 119.3, 117.0, 66.6, 62.3, 22.9, 14.1 ppm;
HRMS (ESI-TOF): m/z calcd for C19H20NO4 [M+H]+ 326.1387, found 326.1392.
Ethyl 3-Acetyl-6-phenyl-2-(trifluoromethyl)isonicotinate (3ag). White solid; 42 mg, 62% yield;
Rf = 0.4 (petroleum ether/ethyl acetate = 15:1); mp 94–96 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.44 (s, 1H), 8.12 (dd, J = 7.6, 2.0 Hz, 2H), 7.56–7.51 (m, 3H), 4.45 (q, J = 7.2 Hz, 2H), 2.67
(s, 3H), 1.43 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 187.4 (q, J =
37.8 Hz), 164.8, 159.9, 156.2, 138.0, 137.4, 130.3, 129.0, 127.3, 127.1, 116.7, 115.7 (q, J = 292.3
Hz), 63.3, 22.6, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for C17H15NO3F3 [M+H]+ 338.0999,
found 338.1008.
Ethyl 3-(Furan-2-carbonyl)-6-phenyl-2-(trifluoromethyl)isonicotinate (3ah). Yellow solid; 58
mg, 75% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); mp 144–146 C; 1H NMR (400
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MHz, Chloroform-d): δ 8.52 (s, 1H), 8.17 (dd, J = 7.6, 2.0 Hz, 2H), 7.59 (s, 1H), 7.57–7.52 (m,
3H), 7.14 (s, 1H), 6.59 (dd, J = 3.6, 1.6 Hz, 1H), 4.27 (qd, J = 7.1, 1.9 Hz, 2H), 1.20 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 180.2, 163.7, 158.6, 153.0, 147.1, 145.8 (q,
J = 34.9 Hz), 140.0, 136.1, 130.9, 130.5, 129.2, 127.3, 122.6, 121.1 (q, J = 277.4 Hz), 118.3, 112.8,
62.9, 13.6 ppm; HRMS (ESI-TOF): m/z calcd for C20H15NO4F3 [M+H]+ 390.0948, found
390.0969.
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Ethyl 3-Benzoyl-6-phenyl-2-(trifluoromethyl)isonicotinate (3ai). White solid; 66 mg, 83% yield;
Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); mp 119–120 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.55 (s, 1H), 8.18 (dd, J = 7.7, 1.8 Hz, 2H), 7.79 (d, J = 7.5 Hz, 2H), 7.62–7.53 (m, 4H), 7.48
(t, J = 7.8 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, Chloroform-d): δ 192.7, 163.6, 158.4, 145.8(q, J = 34.8 Hz), 137.2, 136.2, 133.7, 131.8,
130.8, 129.2, 128.9, 128.7, 127.3, 122.7, 121.1 (q, J = 277.5 Hz), 76.8, 62.9, 13.5 ppm; HRMS
(ESI-TOF): m/z calcd for C22H17NO3F3 [M+H]+ 400.1155, found 400.1174.
Ethyl 3-Benzoyl-6-(4-chlorophenyl)-2-(trifluoromethyl)isonicotinate (3ci). White solid; 50 mg,
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58% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 8:1); mp 131–132 C; H NMR (400 MHz,
Chloroform-d): δ 8.51 (s, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.4
Hz, 1H), 7.54–7.50 (m, 2H), 7.47 (t, J = 7.8 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.07 (t, J = 7.2 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 192.4, 163.5, 157.1, 146.0 (q, J = 34.9 Hz),
139.9, 137.2, 137.1, 134.6, 133.8, 132.1, 129.4, 128.9, 128.7, 128.6, 122.4, 121.0 (q, J = 277.4
Hz), 62.9, 13.5 ppm; HRMS (ESI-TOF): m/z calcd for C22H16NO3F3Cl [M+H]+ 434.0765, found
434.0738.
Ethyl 3-Benzoyl-6-(p-tolyl)-2-(trifluoromethyl)isonicotinate (3fi). White solid; 58 mg, 70% yield;
Rf = 0.4 (petroleum ether/ethyl acetate = 8:1); mp 124–126 oC; 1H NMR (400 MHz, Chloroform-
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d): δ 8.51 (s, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47
(t, J = 7.8 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.07 (t, J = 7.2
Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 192.8, 163.7, 158.4, 145.8 (q, J = 34.4
Hz), 141.3, 139.6, 137.2, 133.7, 133.5, 131.4, 129.9, 128.9, 128.7, 127.2, 121.1 (q, J = 277.5 Hz),
122.3, 62.8, 21.5, 13.5 ppm; HRMS (ESI-TOF): m/z calcd for C23H19NO3F3 [M+H]+ 414.1312,
found 414.1324.
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Ethyl 3-Benzoyl-6-(2-methoxyphenyl)-2-(trifluoromethyl)isonicotinate (3ki). White solid; 52 mg,
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60% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 8:1); mp 122–124 C; H NMR (400 MHz,
Chloroform-d): δ 8.79 (s, 1H), 8.05 (dd, J = 7.7, 1.7 Hz, 1H), 7.81 (d, J = 7.4 Hz, 2H), 7.60 (t, J =
7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 3H), 7.15 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.16 (q, J
= 7.1 Hz, 2H), 3.95 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-
d): δ 192.9, 163.9, 157.6, 157.2, 145.3 (q, J = 34.6 Hz), 138.5, 137.3, 133.6, 131.8, 131.5, 131.3,
128.9, 128.7, 127.8, 125.8, 121.4, 121.2 (q, J = 277.4 Hz), 111.6, 62.6, 55.7, 13.5 ppm; HRMS
(ESI-TOF): m/z calcd for C23H19NO4F3 [M+H]+ 430.1261, found 430.1288.
Ethyl 3-Benzoyl-6-(naphthalen-2-yl)-2-(trifluoromethyl)isonicotinate (3mi). Yellow solid; 58
o
mg, 65% yield; Rf = 0.2 (petroleum ether/ethyl acetate = 10:1); mp 129–131 C; 1H NMR (400
MHz, Chloroform-d): δ 8.66 (d, J = 7.3 Hz, 2H), 8.28 (dd, J = 8.6, 1.8 Hz, 1H), 7.99 (d, J = 8.4
Hz, 2H), 7.92–7.87 (m, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.62–7.54 (m, 3H), 7.48 (t, J = 7.8 Hz, 2H),
4.20 (q, J = 7.1 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d) δ
192.7, 163.7, 158.3, 145.9 (q, J = 34.7 Hz), 139.7, 137.2, 134.5, 133.7, 133.5, 133.3, 131.7, 129.1,
129.1, 128.9, 128.8, 127.8, 127.6, 127.5, 126.8, 124.0, 122.9, 121.2 (q, J = 277.5 Hz), 62.9, 13.5
ppm; HRMS (ESI-TOF): m/z calcd for C26H19NO3F3 [M+H]+ 450.1312, found 450.1326.
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Ethyl 5-Oxo-2-phenyl-5,6,7,8-tetrahydroquinoline-4-carboxylate (3aj). White solid; 40 mg, 68%
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yield; Rf = 0.2 (petroleum ether/ethyl acetate = 5:1); mp 114–115 C; H NMR (400 MHz,
Chloroform-d): δ 8.08 – 8.02 (m, 2H), 7.60 (s, 1H), 7.49 (dd, J = 5.2, 2.0 Hz, 3H), 4.48 (q, J = 7.2
Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 2.76–2.70 (m, 2H), 2.26–2.20 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H)
ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 196.5, 168.8, 164.6, 160.7, 142.9, 137.6, 130.5,
129.0, 127.5, 122.8, 116.9, 62.3, 38.6, 33.2, 21.6, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for
C18H18NO3 [M+H]+ 296.1281, found 296.1288.
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Ethyl 5-Oxo-2-phenyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-4-carboxylate (3ak). White solid;
38 mg, 64% yield; Rf = 0.2 (petroleum ether/ethyl acetate = 5:1); mp 134–135 oC; 1H NMR (400
MHz, Chloroform-d): δ 8.06 (d, J = 3.4 Hz, 2H), 7.73 (s, 1H), 7.55–7.48 (m, 3H), 5.02 (s, 2H),
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4.49 (q, J = 7.1 Hz, 2H), 4.42 (s, 2H), 1.42 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz,
Chloroform-d): δ 192.1, 167.6, 161.7, 161.5, 142.0, 137.1, 131.0, 127.6, 120.3, 117.8, 73.0, 62.6,
14.0 ppm; HRMS (ESI-TOF): m/z calcd for C17H16NO4 [M+H]+ 298.1074, found 298.1088.
Ethyl 7,7-Dimethyl-5-oxo-2-phenyl-5,6,7,8-tetrahydroquinoline-4-carboxylate (3al). White
solid; 39 mg, 60% yield; Rf = 0.2 (petroleum ether/ethyl acetate = 5:1); mp 100–102 oC; 1H NMR
(400 MHz, Chloroform-d): δ 8.05 (dd, J = 7.4, 2.3 Hz, 2H), 7.60 (s, 1H), 7.49 (dd, J = 5.3, 1.9 Hz,
3H), 4.48 (q, J = 7.2 Hz, 2H), 3.14 (s, 2H), 2.60 (s, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.16 (s, 6H) ppm;
13C{1H} NMR (101 MHz, Chloroform-d): δ 196.7, 168.8, 163.2, 161.1, 137.6, 130.5, 129.0, 127.5,
121.9, 116.8, 62.3, 52.2, 47.0, 33.0, 28.3, 14.0 ppm; HRMS (ESI-TOF): m/z calcd for C20H22NO3
[M+H]+ 324.1594, found 324.1602.
Ethyl 5-Oxo-2-phenyl-5H-indeno[1,2-b]pyridine-4-carboxylate (3am). Yellow solid; 22 mg, 34%
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yield; Rf = 0.2 (petroleum ether/ethyl acetate = 5:1); mp 109–110 C; H NMR (400 MHz,
Chloroform-d): δ 8.17 (dd, J = 7.7, 1.8 Hz, 2H), 7.98 (d, J = 7.4 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J
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= 7.4 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 7.1 Hz, 3H), 7.47 (t, J = 7.5 Hz, 1H), 4.53 (q,
J = 7.1 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 189.0,
166.0, 165.5, 162.1, 142.8, 138.2, 137.7, 135.4, 135.1, 131.4, 130.6, 129.0, 127.5, 124.1, 123.1,
121.2, 118.3, 62.5 ppm; HRMS (ESI-TOF): m/z calcd for C21H16NO3 [M+H]+ 330.1125, found
330.1126.
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Ethyl 3-Benzoyl-2,6-diphenylisonicotinate (3an). White solid; 34 mg, 42% yield; Rf = 0.4
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(petroleum ether/ethyl acetate = 5:1); mp 97–99 C; H NMR (400 MHz, Chloroform-d): δ 8.20
(s, 1H), 8.10 (d, J = 6.9 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H), 7.45 (dd, J = 6.5, 3.0 Hz, 2H), 7.41 (s,
1H), 7.40–7.34 (m, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7.7 Hz, 2H), 7.14 (dd, J = 4.5, 2.3
Hz, 3H), 4.09 (q, J = 7.1 Hz, 2H), 1.00 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
Chloroform-d): δ 196.4, 165.3, 158.0, 157.3, 139.3, 139.1, 137.8, 137.5, 133.2, 132.3, 130.0, 129.4,
129.0, 129.0, 128.8, 128.5, 128.1, 127.3, 118.1, 62.4, 13.6 ppm; HRMS (ESI-TOF): m/z calcd for
C27H22NO3 [M+H]+ 408.1594, found 408.1600.
Ethyl 2,6-Diphenylisonicotinate (3an′). White solid; 18 mg, 30% yield; Rf = 0.4 (petroleum
ether/ethyl acetate = 10:1); mp 105–107 oC; 1H NMR (400 MHz, Chloroform-d): δ 8.26 (s, 2H),
8.21 (dd, J = 8.3, 1.3 Hz, 4H), 7.56–7.45 (m, 6H), 4.49 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H)
ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 165.6, 157.8, 139.5, 138.7, 129.5, 128.8, 127.1,
117.8, 61.9, 14.3 ppm; HRMS (ESI-TOF): m/z calcd for C20H18NO2 [M+H]+ 304.1332, found
304.1344.
1-(2-Methyl-4,6-diphenylpyridin-3-yl)ethan-1-one (3qa). White solid; 35 mg, 62% yield; Rf = 0.2
(petroleum ether/ethyl acetate = 10:1); mp 94–96 oC; 1H NMR (400 MHz, Chloroform-d): δ 8.06–
8.02 (m, 2H), 7.58 (s, 1H), 7.49–7.40 (m, 8H), 2.63 (s, 3H), 2.01 (s, 3H) ppm; 13C{1H} NMR (101
MHz, Chloroform-d): δ 206.4, 157.0, 154.1, 147.3, 138.8, 138.4, 134.5, 129.3, 129.0, 129.0, 128.8,
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128.5, 127.1, 118.6, 32.1, 23.1 ppm; HRMS (ESI-TOF): m/z calcd for C20H18NO [M+H]+
288.1383, found 288.1384.
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1-(2,6-Dimethyl-4-phenylpyridin-3-yl)ethan-1-one (3ra). Yellow oil; 24 mg, 53% yield; Rf = 0.3
(petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, Chloroform-d): δ 7.44–7.41 (m, 3H),
7.33 (dd, J = 6.6, 3.0 Hz, 2H), 7.02 (s, 1H), 2.58 (s, 3H), 2.52 (s, 3H), 1.95 (s, 3H) ppm; 13C{1H}
NMR (101 MHz, Chloroform-d): δ 206.5, 158.2, 153.4, 146.9, 138.2, 133.5, 129.0, 128.9, 128.4,
121.2, 32.2, 24.4, 22.7 ppm; HRMS (ESI-TOF): m/z calcd for C15H16NO [M+H]+ 226.1226, found
226.1224.
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1-(2-Methyl-6-phenyl-4-propylpyridin-3-yl)ethan-1-one (3sa). Yellow oil; 18 mg, 35% yield; Rf
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= 0.4 (petroleum ether/ethyl acetate = 10:1); H NMR (400 MHz, Chloroform-d): δ 7.97 (d, J =
8.2 Hz, 2H), 7.46 (q, J = 7.7, 7.1 Hz, 3H), 7.41 (s, 1H), 2.55 (d, J = 2.3 Hz, 6H), 2.53 (d, J = 8.7
Hz, 2H), 1.67 (dq, J = 15.1, 7.5 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
Chloroform-d): δ 206.7, 156.9, 152.5, 147.6, 139.1, 135.9, 129.1, 128.8, 127.1, 118.6, 34.9, 32.7,
23.9, 22.9, 14.1 ppm; HRMS (ESI-TOF): m/z calcd for C17H20NO [M+H]+ 254.1539, found
254.1540.
2-Methyl-N,4,6-triphenylnicotinamide (3qo). White solid; 49 mg, 67% yield; Rf = 0.4 (petroleum
ether/ethyl acetate = 10:1); mp 239–240 oC; 1H NMR (400 MHz, Chloroform-d): δ 8.03 (d, J = 6.9
Hz, 2H), 7.63–7.51 (m, 3H), 7.51–7.36 (m, 6H), 7.24 (d, J = 9.3 Hz, 4H), 7.14–7.02 (m, 2H), 2.78
(s, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 167.0, 157.5, 156.4, 147.7, 138.8, 138.0,
137.1, 129.4, 129.0, 128.9, 128.1, 127.2, 125.0, 120.5, 118.6, 23.2 ppm; HRMS (ESI-TOF): m/z
calcd for C25H21N2O [M+H]+ 365.1648, found 365.1658.
2-Methyl-N,6-diphenyl-4-propylnicotinamide (3so). White solid; 30 mg, 45% yield; Rf = 0.4
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(petroleum ether/ethyl acetate = 15:1); mp 205–206 C; H NMR (400 MHz, Chloroform-d): δ
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7.96 (d, J = 6.9 Hz, 2H), 7.86 (s, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.1 Hz, 2H), 7.45–7.39
(m, 3H), 7.37 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H), 2.65 (s, 3H), 2.55–2.50 (m, 2H), 1.66 (dq, J = 14.9,
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7.5 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 167.2,
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157.1, 154.4, 149.3, 139.0, 137.6, 131.2, 129.3, 129.2, 128.8, 127.1, 125.0, 120.0, 118.3, 34.8,
23.6, 22.8, 14.1 ppm; HRMS (ESI-TOF): m/z calcd for C22H23N2O [M+H]+ 331.1805, found
331.1816.
Ethyl 2-Phenyl-6-(trifluoromethyl)isonicotinate (5a). White solid; 50 mg, 85% yield; Rf = 0.4
(petroleum ether/ethyl acetate = 20:1); mp 66–68 oC; 1H NMR (400 MHz, Chloroform-d): δ 8.48
(s, 1H), 8.15–8.11 (m, 3H), 7.51 (t, J = 7.3 Hz, 3H), 4.49 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 163.1, 157.9, 148.0 (q, J = 35.3 Hz), 139.2,
135.9, 129.3, 128.0, 126.2, 121.2, 120.3 (q, J = 275.6 Hz), 116.8 (q, J = 2.8 Hz), 61.4, 13.2 ppm;
HRMS (ESI-TOF): m/z calcd for C15H13NO2F3 [M+H]+ 296.0893, found 296.0907.
Ethyl 2-(4-Fluorophenyl)-6-(trifluoromethyl)isonicotinate (5b). Light yellow solid; 43 mg, 68%
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yield; Rf = 0.4 (petroleum ether/ethyl acetate = 20:1); mp 100–101 C; H NMR (400 MHz,
Chloroform-d): δ 8.34 (s, 1H), 8.06–8.02 (m, 3H), 7.11 (t, J = 8.6 Hz, 2H), 4.41 (q, J = 7.1 Hz,
2H), 1.38 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 165.5 (d, J = 252
Hz), 164.0, 157.8, 149.1 (q, J = 35.4 Hz), 140.4, 133.1 (d, J = 3.1 Hz), 129.3 (d, J = 8.7 Hz), 121.9,
121.3 (q, J = 275.5 Hz), 117.8 (q, J = 2.7 Hz), 116.2 (d, J = 21.9 Hz), 62.5, 14.2 ppm; HRMS (ESI-
TOF): m/z calcd for C15H12NO2F4 [M+H]+ 314.0799, found 314.0819.
Ethyl 2-(4-Chlorophenyl)-6-(trifluoromethyl)isonicotinate (5c). White solid; 40 mg, 61% yield;
Rf = 0.4 (petroleum ether/ethyl acetate = 20:1); mp 96–97 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.43 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 4.49 (q, J = 7.1
Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 163.9, 157.7,
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149.2 (q, J = 35.4 Hz), 140.4, 136.6, 135.3, 129.2, 128.5, 121.9, 121.2 (q, J = 275.5 Hz), 118.1 (q,
J = 2.8 Hz), 62.5, 14.2 ppm; HRMS (ESI-TOF): m/z calcd for C15H12NO2F3Cl [M+H]+ 330.0503,
found 330.0518.
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Ethyl 2-(4-Cyanophenyl)-6-(trifluoromethyl)isonicotinate (5d). White solid; 40 mg, 62% yield;
Rf = 0.3 (petroleum ether/ethyl acetate = 20:1); mp 118–119 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.52 (s, 1H), 8.25 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 1.1 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 4.50
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(q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ
163.7, 156.7, 149.5 (q, J = 35.6 Hz), 140.9, 132.8, 127.8, 122.7, 121.1 (q, J = 275.7 Hz), 119.1 (q,
J = 2.7 Hz), 118.4, 113.9, 62.7, 14.2 ppm; HRMS (ESI-TOF): m/z calcd for C16H12N2O2F3 [M+H]+
321.0845, found 321.0862.
Ethyl 2-(4-Nitrophenyl)-6-(trifluoromethyl)isonicotinate (5e). White solid; 40 mg, 59% yield; Rf
= 0.3 (petroleum ether/ethyl acetate = 20:1); mp 123–124 oC; 1H NMR (400 MHz, Chloroform-d):
δ 8.55 (s, 1H), 8.38–8.29 (m, 4H), 8.23 (s, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H)
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ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 163.6, 156.3, 149.6 (q, J = 35.7 Hz), 148.9,
142.6, 140.9, 128.2, 124.2, 122.9, 121.1 (q, J = 275.7 Hz), 119.3 (q, J = 2.7 Hz), 62.7, 14.2 ppm;
HRMS (ESI-TOF): m/z calcd for C15H12N2O4F3 [M+H]+ 341.0744, found 341.0768.
Ethyl 2-(p-Tolyl)-6-(trifluoromethyl)isonicotinate (5f). White solid; 50 mg, 81% yield; Rf = 0.4
(petroleum ether/ethyl acetate = 20:1); mp 81–83 oC; 1H NMR (400 MHz, Chloroform-d): δ 8.44
(s, 1H), 8.09 (s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H),
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2.42 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 163.1,
157.9, 147.9 (q, J = 35 Hz), 139.6, 139.1, 133.2, 128.7, 126.0, 120.8, 120.3 (q, J = 275.5 Hz),
116.4 (q, J = 2.8 Hz), 61.3, 20.3, 13.2 ppm; HRMS (ESI-TOF): m/z calcd for C16H15NO2F3
[M+H]+ 310.1049, found 310.1062.
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Ethyl 2-(4-Methoxyphenyl)-6-(trifluoromethyl)isonicotinate (5g). White solid; 42 mg, 65% yield;
Rf = 0.3 (petroleum ether/ethyl acetate = 20:1); mp 81–82 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.40 (s, 1H), 8.08 (d, J = 9.0 Hz, 2H), 8.04 (d, J = 1.1 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 4.47
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164.3, 161.5, 158.6, 148.9 (q, J = 35.1 Hz), 140.0, 129.5, 128.7, 121.4, 121.4 (q, J = 275.6 Hz),
116.9 (q, J = 2.8 Hz), 114.4, 62.3, 55.4, 14.2 ppm; HRMS (ESI-TOF): m/z calcd for C16H15NO3F3
[M+H]+326.0999, found 326.1022.
Ethyl 2-(3-Bromophenyl)-6-(trifluoromethyl)isonicotinate (5h). White solid; 48 mg, 65% yield;
Rf = 0.4 (petroleum ether/ethyl acetate = 20:1); mp 103–105 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.44 (s, 1H), 8.27 (t, J = 1.7 Hz, 1H), 8.16 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.9
Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}
NMR (101 MHz, Chloroform-d): δ 163.9, 157.3, 149.2 (q, J = 35.6 Hz), 140.5, 138.9, 133.3, 130.5,
130.3, 125.8, 123.3, 122.3, 121.2 (q, J = 275.7 Hz), 118.5 (q, J = 2.8 Hz), 62.6, 14.2 ppm; HRMS
(ESI-TOF): m/z calcd for C15H12NO2F3Br [M+H]+ 373.9998, found 374.0000.
Ethyl 2-(3-Methoxyphenyl)-6-(trifluoromethyl)isonicotinate (5i). White solid; 52 mg, 80% yield;
Rf = 0.3 (petroleum ether/ethyl acetate = 20:1); mp 154–155 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.46 (s, 1H), 8.13 (s, 1H), 7.74–7.64 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.08–7.00 (m, 1H),
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4.49 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz,
Chloroform-d): δ 164.1, 160.2, 158.7, 149.0 (q, J = 35.3 Hz), 140.2, 138.4, 130.0, 122.4, 121.3 (q,
J = 275.5 Hz), 119.6, 118.0 (q, J = 2.8 Hz), 116.1, 112.7, 62.4, 55.5, 14.2 ppm; HRMS (ESI-TOF):
m/z calcd for C16H15NO3F3 [M+H]+ 326.0999, found 326.1013.
Ethyl 2-(2-Methoxyphenyl)-6-(trifluoromethyl)isonicotinate (5j). White solid; 39 mg, 60% yield;
Rf = 0.3 (petroleum ether/ethyl acetate = 20:1); mp 81–83 oC; 1H NMR (400 MHz, Chloroform-
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d): δ 8.66 (s, 1H), 8.11 (s, 1H), 7.93 (dd, J = 7.7, 1.8 Hz, 1H), 7.47–7.40 (m, 1H), 7.11 (td, J = 7.6,
1.0 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.45 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 164.4, 157.8, 157.3, 148.6 (q, J = 35.2 Hz),
139.0, 131.4, 131.3, 127.3, 126.7, 121.4 (q, J = 275.4 Hz), 121.3, 117.4 (q, J = 2.9 Hz), 111.5,
62.2, 55.6, 14.2 ppm; HRMS (ESI-TOF): m/z calcd for C16H15NO3F3 [M+H]+ 326.0999, found
326.1014.
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Ethyl 2-([1,1'-Biphenyl]-4-yl)-6-(trifluoromethyl)isonicotinate (5k). White solid; 30 mg, 40%
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yield; Rf = 0.3 (petroleum ether/ethyl acetate = 20:1); mp 152–154 C; H NMR (400 MHz,
Chloroform-d): δ 8.53 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 8.14 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.66
(d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.48
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(t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 164.2, 158.6, 149.1 (q, J =
35.3 Hz), 143.1, 140.3, 140.2, 135.8, 128.9, 127.9, 127.7, 127.7, 127.2, 122.1, 121.3 (q, J = 275.6
Hz), 117.8 (q, J = 2.8 Hz), 117.8, 62.5, 14.3 ppm; HRMS (ESI-TOF): m/z calcd for C21H17NO2F3
[M+H]+ 372.1206, found 372.1195.
Ethyl 2-(Naphthalen-2-yl)-6-(trifluoromethyl)isonicotinate (5l). White solid; 57 mg, 82% yield;
Rf = 0.3 (petroleum ether/ethyl acetate = 20:1); mp 191–192 oC; 1H NMR (400 MHz, Chloroform-
d): δ 8.49 (s, 2H), 8.14 (dd, J = 8.6, 1.8 Hz, 1H), 8.03 (d, J = 1.1 Hz, 1H), 7.86 (t, J = 8.2 Hz, 2H),
7.79–7.75 (m, 1H), 7.46–7.40 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, Chloroform-d): δ 164.1, 158.8, 149.1 (q, J = 35.3 Hz), 140.3, 134.2,
133.3, 129.0, 128.8, 127.7, 127.3, 127.2, 126.6, 124.2, 122.4, 121.4 (q, J = 275.6 Hz), 117.8 (q, J
= 2.8 Hz), 62.4, 14.3 ppm; HRMS (ESI-TOF): m/z calcd for C19H15NO2F3 [M+H]+ 346.1049,
found 346.1065.
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Ethyl 2-(Thiophen-2-yl)-6-(trifluoromethyl)isonicotinate (5m). White solid; 31mg, 52% yield; Rf
= 0.4 (petroleum ether/ethyl acetate = 20:1); mp 80–82 oC; 1H NMR (400 MHz, Chloroform-d): δ
8.32 (s, 1H), 8.01 (d, J = 0.9 Hz, 1H), 7.78 (d, J = 3.7 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H), 7.15 (dd,
J = 5.0, 3.8 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, Chloroform-d): δ 164.0, 154.3, 148.9(q, J = 35.4 Hz), 142.4, 140.1, 129.6, 128.4, 126.9,
121.1 (q, J = 275.6 Hz), 120.8, 117.3 (q, J = 2.8 Hz), 62.5, 14.2 ppm; HRMS (ESI-TOF): m/z
calcd for C13H11NO2F3S [M+H]+ 302.0457, found 302.0475.
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4-Methyl-2,6-Diphenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7a). White solid; 50 mg, 80%
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yield; Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); mp 166–168 C; H NMR (400 MHz,
Chloroform-d): δ 8.14 (dd, J = 7.3, 2.1 Hz, 2H), 8.09 (s, 1H), 7.56–7.50 (m, 5H), 7.44 (d, J = 7.7
Hz, 3H), 3.01 (s, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 167.2, 166.1, 162.8, 157.5,
141.0, 137.7, 131.4, 130.8, 129.2, 129.1, 128.4, 127.7, 126.6, 120.5, 111.6, 21.6 ppm; HRMS (ESI-
TOF): m/z calcd for C20H15N2O2 [M+H]+ 315.1128, found 315.1140.
6-(4-Fluorophenyl)-4-methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7b). Light
yellow solid; 60 mg, 90% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); mp 180–182 oC;
1H NMR (400 MHz, Chloroform-d): δ 8.16 (dd, J = 8.8, 5.4 Hz, 2H), 8.04 (s, 1H), 7.56–7.48 (m,
2H), 7.43 (dd, J = 7.7, 1.7 Hz, 3H), 7.21 (t, J = 8.6 Hz, 2H), 2.99 (s, 3H) ppm; 13C{1H} NMR (101
MHz, Chloroform-d): δ 167.1, 166.0, 165.8(d, J = 252.8 Hz), 163.3, 161.6, 141.1, 133.9(d, J = 3.2
Hz), 131.3, 129.8 (d, J = 8.7 Hz) ,129.2, 128.5, 126.6, 120.5, 116.3 (d, J = 21.9 Hz), 111.2, 21.6
ppm; HRMS (ESI-TOF): m/z calcd for C20H14N2O2F [M+H]+ 333.1034, found 333.1056.
6-(4-Chlorophenyl)-4-methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7c). White
solid; 58 mg, 83% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); mp 238–239 oC; 1H NMR
(400 MHz, Chloroform-d): δ 8.10 (d, J = 8.5 Hz, 2H), 8.06 (s, 1H), 7.51 (t, J = 7.9 Hz, 4H), 7.44
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(d, J = 7.9 Hz, 3H), 3.00 (s, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 167.0, 166.0,
161.5, 157.7, 141.2, 137.1, 136.1, 131.3, 129.3, 129.2, 128.9, 128.5, 126.6, 120.8, 111.3, 21.6 ppm;
HRMS (ESI-TOF): m/z calcd for C20H14N2O2Cl [M+H]+ 349.0755, found 349.0738.
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4-(4-Methyl-1,3-dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)benzonitrile (7d).
Light yellow solid; 49 mg, 72% yield; Rf = 0.2 (petroleum ether/ethyl acetate = 10:1); mp 263–
265 oC; 1H NMR (400 MHz, Chloroform-d): δ 8.28 (d, J = 8.5 Hz, 2H), 8.15 (s, 1H), 7.83 (d, J =
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8.5 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 3H), 3.03 (s, 3H) ppm; C{1H} NMR
(101 MHz, Chloroform-d) δ 166.8, 165.7, 160.4, 158.0, 141.6, 141.4, 132.8, 131.2, 129.3, 128.6,
128.2, 126.5, 121.7, 118.4, 114.2, 112, 21.5 ppm; HRMS (ESI-TOF): m/z calcd for C21H14N3O2
calcd for C21H14N3O2 [M+H]+ 340.1081, found 340.1093.
4-Methyl-6-(4-nitrophenyl)-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7e). Yellow
solid; 50 mg, 70% yield; Rf = 0.2 (petroleum ether/ethyl acetate = 10:1); mp 195–197 oC; 1H NMR
(400 MHz, Chloroform-d): δ 8.36 (q, J = 9.0 Hz, 4H), 8.19 (s, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.45
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(t, J = 7.0 Hz, 3H), 3.05 (s, 3H) ppm; C{1H} NMR (101 MHz, Chloroform-d): δ 166.8, 165.7,
160.0, 158.1, 149.1, 143.3, 141.4, 131.2, 129.3, 128.6, 128.6, 126.5, 124.2, 121.9, 112.3, 21.6 ppm;
HRMS (ESI-TOF): m/z calcd for C20H14N3O4 [M+H]+ 360.0979, found 360.0990.
4-Methyl-2-phenyl-6-(p-tolyl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7f). Light yellow solid;
53 mg, 80% yield; Rf = 0.3 (petroleum ether/ethyl acetate = 10:1); mp 204–206 oC; 1H NMR (400
MHz, Chloroform-d): δ 8.08–8.02 (m, 3H), 7.55–7.49 (m, 2H), 7.44 (d, J = 8.2 Hz, 3H), 7.32 (d,
J = 8.0 Hz, 2H), 2.99 (s, 3H), 2.43 (s, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 167.2,
166.2, 162.7, 157.4, 141.2, 140.9, 135.0, 131.5, 129.8, 129.2, 128.3, 127.6, 126.6, 120.1, 111.1,
21.6, 21.4 ppm; HRMS (ESI-TOF): m/z calcd for C21H17N2O2 [M+H]+ 329.1290, found 329.1304.
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(7g).
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Yellow solid; 63 mg, 92% yield; Rf = 0.3 (petroleum ether/ethyl acetate = 10:1); mp 175–177 oC;
1H NMR (400 MHz, Chloroform-d): δ 8.14 (d, J = 8.9 Hz, 2H), 8.04 (s, 1H), 7.55–7.50 (m, 2H),
7.44 (d, J = 7.8 Hz, 3H), 7.04 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H), 2.98 (s, 3H) ppm; 13C{1H} NMR
(101 MHz, Chloroform-d): δ 167.3, 166.3, 162.3, 162.0, 157.4, 140.9, 131.5, 130.3, 129.2, 129.2,
128.3, 126.6, 119.6, 114.5, 110.6, 55.5, 21.6 ppm; HRMS (ESI-TOF): m/z calcd for C21H17N2O3
[M+H]+ 345.1234, found 345.1249.
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6-(3-Bromophenyl)-4-methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7h). White
solid; 54 mg, 69% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 15:1); mp 191–193 oC; 1H NMR
(400 MHz, Chloroform-d): δ 8.33 (s, 1H), 8.05 (d, J = 10.9 Hz, 2H), 7.66–7.61 (m, 1H), 7.56–7.50
(m, 2H), 7.47–7.37 (m, 4H), 3.01 (s, 3H) ppm; 13C{1H} NMR (101 MHz, Chloroform-d): δ 167.0,
161.1, 157.7, 141.2, 139.6, 133.6, 131.3, 130.7, 130.6, 129.2, 128.5, 126.6, 126.1, 123.4, 121.1,
111.6, 21.6 ppm; HRMS (ESI-TOF): m/z calcd for C20H14N2O2Br [M+H]+ 393.0233, found
393.0246.
6-(3-Methoxyphenyl)-4-methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7i). White
solid; 47 mg, 69% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 10:1); mp 206–207 oC; 1H NMR
(400 MHz, Chloroform-d): δ 8.07 (s, 1H), 7.75 –7.66 (m, 2H), 7.57–7.49 (m, 2H), 7.49–7.39 (m,
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4H), 7.06 (dd, J = 8.0, 2.0 Hz, 1H), 3.91 (s, 3H), 3.00 (s, 3H) ppm; C{1H} NMR (101 MHz,
Chloroform-d): δ 167.2, 166.1, 162.6, 160.3, 157.5, 141.0, 139.1, 131.4, 130.1, 129.2, 128.4, 126.6,
120.6, 120.0, 116.8, 112.8, 111.7, 55.5, 21.6 ppm; HRMS (ESI-TOF): m/z calcd for C21H17N2O3
[M+H]+ 345.1234, found 345.1211.
6-(2-Fluorophenyl)-4-methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (7j). White
solid; 40 mg, 60% yield; Rf = 0.4 (petroleum ether/ethyl acetate = 20:1); mp 198–200 oC; 1H NMR
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