A new strategy for facile synthesis of tetrasubstituted pyridine derivatives

Article abstract of DOI:10.1016/j.tet.2013.06.082

A facile and efficient reaction of α-azidomethyl aryl ketones and dialkyl but-2-ynedioate offers a new strategy for the synthesis of tetrasubstituted pyridines in mild condition. This method tolerates a range of functionality and a possible mechanism is proposed.

Full text of DOI:10.1016/j.tet.2013.06.082

Accepted Manuscript
A New Strategy for Facile Synthesis of Tetrasubstituted Pyridine Derivatives
Jun Chen, Hangcheng Ni, Wenteng Chen, Guolin Zhang, Yongping Yu
PII:
S0040-4020(13)01041-7
10.1016/j.tet.2013.06.082
TET 24558
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 April 2013
Revised Date: 18 June 2013
Accepted Date: 24 June 2013
Please cite this article as: Chen J, Ni H, Chen W, Zhang G, Yu Y, A New Strategy for Facile Synthesis of
Tetrasubstituted Pyridine Derivatives, Tetrahedron (2013), doi: 10.1016/j.tet.2013.06.082.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
A New Strategy for Facile Synthesis of Tetrasubstituted
Pyridine Derivatives
Leave this area blank for abstract info.
Jun Chen, Hangcheng Ni, Wenteng Chen, Guolin Zhang*and Yongping Yu*
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou
310058, .China

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
A New Strategy for Facile Synthesis of Tetrasubstituted Pyridine Derivatives
Jun Chen, Hangcheng Ni, Wenteng Chen, Guolin Zhang*and Yongping Yu*
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, .China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and efficient reaction of α-azidomethyl aryl ketones and dialkyl but-2-
ynedioate offers a new strategy for the synthesis of tetrasubstituted pyridines in mild
condition. This method tolerates a range of functionality and a possible mechanism is
proposed.
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords:
pyridine
azidoketone
alkyne
heterocycle
cyclization
1. Introduction
due to the strong power of the “Click Chemistry”, there are
fewer studies on the reaction of azides and alkynes under
other reacion conditions. P. Shanmugavelan et al. reported the
Substituted pyridines are one of the most prevalent
heterocycles in natural products,
various kinds of functional materials. Over the past decades, a
variety of synthetic strategies have been developed to obtain
substituted pyridines, including copper-catalyzed coupling of
oxime acetates with aldehydes, [4] rhodium-catalyzed coupling of
[1]
[2]
pharmaceuticals,
and
formation of 1,2,3-triazoles from α-azidomethyl aryl ketones and
[3]
[13]
alkynes in metal-free condtion. (Scheme 1A)
Here, we
explored a different, efficient and novel reaction from α-
azidomethyl aryl ketones and alkyne to afford tetrasubstituted
pyridines under a relatively mild, metal-free reaction conditions.
(Scheme 1B)
[5]
[6]
ketoximes and alkynes,
Bohlmann-Rahtz reaction,
microwave-assisted condensation,
[7]
condensation of ketoximines and
alkenylboronic acids [8] and so on.[9] The existing methods require
transition metal catalysts and harsh reaction conditions.
Therefore, versatile and efficient methods for the construction of
pyridine rings which are compatible with functional groups and
utilize readily available starting materials remain highly desirable.
α-azidomethyl aryl ketones are a pivotal synthon for new
scaffold construction. In the past decades, a plethora of reactions
[10]
have been reported in the literature.
We have utilized the α-
azidomethyl aryl ketones for the formation of substituted
[11]
imidazole.
As part of an ongoing research program in α-
azidomethyl aryl ketones, we were interested in developing a
novel methodology from this simple synthon.
To the best of our knowledge, CuI-catalyzed synthesis of
1,2,3-triazoles from azides and alkynes, namely “Click
Chemistry” , was widely reported in the literature.[12] However,
Scheme 1 Reaction of α-azidomethyl aryl ketones with electron-deficient
alkynes
2. Results and discussion
Initially, the reaction of α-2-azido-1-phenylethanone and
dimethyl but-2-ynedioate was chosen as the model reaction. No
reaction was observed without any base. (Table 1, entry 10) The
transformation occurred when the reaction was performed in the
presence of a variety of bases. (Table 1)
Corresponding authors. Tel./fax: +86 571 88208450 (Y.Y.);
tel./fax: +86 571 88208452 (G.Z.); e-mail addresses:
yyu@zju.edu.cn (Y. Yu), guolinzhang@zju.edu.cn (G. Zhang).

ACCEPTED MANUSCRIPT
2
Tetrahedron
Entry
1
Ar
C6H5
C6H5
R
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
Product
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Yield [%][b]
Screening of the base and solvent reveals that K2CO3 was the
79
74
75
73
77
79
75
75
72
70
65
60
77
76
73
74
81
81
32
most efficient base and acetonitrile was superior to other protic
and aprotic solvents, (Table 1, entries 1 to 9) but the yield was
significantly reduced when the reaction was performed at 80 C
or at room temperature. (Table 1, entries 11, 12) When only 1.2
equiv. of dimethyl but-2-ynediote was used, the conversion of the
reaction maintained. (Table 1, entry 13). And the yield was less
reduced when only 1 equiv. of dimethyl but-2-ynediote was used.
(Table 1 entry 14) On the basis of this initial study, the optimal
2
3
4-CH3-C6H4
4-CH3-C6H4
4-Br-C6H4
o
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4-Br-C6H4
4-OCH3-C6H4
4-OCH3-C6H4
2-Thiophene
2-Thiophene
2-Cl-C6H4
0
reactivity was obtained in CH3CN at 55 C when 1.2 eqiuv. of
dimethyl but-2-ynedioate was employed in the presence of
K2CO3. (90%; Table 1, entry 13)
2-Cl-C6H4
3-OCH3-C6H4
3-OCH3-C6H4
3,4-diOCH3-C6H3
3,4-diOCH3-C6H3
4-Cl-C6H4
Table 1 Optimization of reaction conditions [a]
4-Cl-C6H4
4-NO2-C6H4
CH3CH2
CH3
3s
[a] Reaction conditions: α-azidomethyl aryl ketones (0.5 mmol, 1.0
equiv.), dialkyl but-2-ynedioate (0.6 mmol, 1.2 equiv.), K2CO3 (1 mmol, 2
equiv.), 2 mL of acetonitrile, 12 h, 55 oC. [b] Isolated yield.
Entry
1
2
3
4
5
6
7
8
Base
Solvent
CH3CN
DMF
EtOH
Toluene
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
T(oC)
55
55
55
55
55
55
55
55
55
55
r.t.
80
55
55
Conversion[d] [%]
Methyl propiolate and methyl 3-phenylpropiolate were also
used under the standard conditon in order to explore the scope of
unsymmetrically substituted alkynes. To our disappointment, no
desired product were observed. (Scheme 2)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
EtONa
Et3N
DBU
/
K2CO3
K2CO3
K2CO3
K2CO3
90
13
16
10
64
80
17
76
80
N.R.
61
76
90
85
9
10
11
12
13[b]
14[c]
[a] Reaction conditions: α-2-azido-1-phenylethanone (0.5 mmol, 1.0 equiv.),
dimethyl but-2-ynedioate (0.6 mmol, 1.2 equiv.), base (1 mmol, 2 equiv.), 2
mL of solvent, 12 h, 55 oC. [b] 0.3 mmol (1.2 equiv.). of dimethyl but-2-
ynedioate was used. [c] 0.25 mmol (1 equiv.) of dimethyl but-2-ynedioate
was used. [d] Determined by high-performance liquid chromatography, based
on the starting α-2-azido-1-phenylethanone. The most successful entry is
highlighted in bold.
Scheme 2. Attempted reaction of asymmetrical alkynes
The structures of the tetrasubstituted pyridines were
1
characterized by H NMR, 13C NMR and HRMS. The structure
of 3i was further proved by X-ray crystal structural analysis as
shown in Fig. 1.
With the optimized reaction conditions in hand, the scope of
the reaction was studied using a set of α-azidomethyl aryl ketones
1, internal alkynes 2. As shown in Table 2, various substituted α-
azidomethyl aryl ketones worked well with internal alkynes to
provide the desired products. Good yields were obtained when 1
contained an electron-donating group and electron-withdrawing
group on the aromatic ring (the isolated yield > 60%). But it gave
lower yields when a strong electron-withdrawing group was
present on the aromatic ring of 1. (Table 2, 3s) Not surprisingly,
heteroaromatic α-azidomethyl aryl ketones were also able to
furnish the desired products in good efficiency. (Table 2, 3i and
3j) The steric effect was also examined in this scope. As
expected, the steric effect on the aromatic ring did influence the
reaction efficiency with a slight reduction in the isolated yield.
(Table 2, 3k compared to 3q and 3l compared 3r)
Table 2 Scope of the reaction [a]
Fig.1 X-Ray crystal structure of 3i

ACCEPTED MANUSCRIPT
3
On the basis of the results presented above, we proposed the
chromatography (Petroleum ether/EtOAc) on slica gel to afford
3a-3s.
following possible mechanism for this reaction, as shown in
Scheme 3. In the presence of base, α-azidomethyl aryl ketone
gave the intermediate (II), which would condense with internal
alkynes (III) to afford the intermediate (V). Another equiv. of (II)
affords the imine intermediate (IV) with a loss of nitrogen,[11] and
cyclization of (IV) and (V) formed intermediate (VI).
Subsequently, (VI) underwent a loss of H2O molecule to form the
intermediate (VII). Aromatization of the resulting (VII) by
kicking off hydrogen azide assisted by a base gave the final
product (VIII). [14]
4.2.1. dimethyl 2-benzoyl-6-phenylpyridine-3,4-dicarboxylate
(3a): white solid, Mp: 123-125 0C. 1H NMR (500 MHz, CDCl3) δ
8.31 (s, 1H), 8.06 (dd, J = 6.7, 3.0 Hz, 2H), 8.01 (dd, J=6.7, 3.0
Hz 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.52 – 7.47 (m, 5H), 4.00 (s,
3H), 3.88 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.58, 166.74,
165.17, 157.73, 154.98, 139.54, 136.62, 135.50, 133.54, 130.87,
130.57, 129.06, 128.32, 127.28, 126.84, 120.45, 53.36, 53.06. IR
(KBr) v: 2952, 1732, 1676, 1584, 1444, 1358 1261, 1100, 950,
804, 759, 691 cm-1. HRMS (ESI) m/z calcd for C22H17NO5
[M+H]+: 376.1179. Found: 376.1182.
4.2.2. diethyl 2-benzoyl-6-phenylpyridine-3,4-dicarboxylate (3b):
white solid. Mp: 87-89 0C. 1H NMR (500 MHz, CDCl3) δ 8.28 (s,
1H), 8.07 (dd, J = 6.5, 3.3 Hz, 2H), 8.03 (dd, J = 8.3, 1.1 Hz, 2H),
7.64 (t, J = 7.4 Hz, 1H), 7.53 – 7.47 (m, 5H), 4.47 (q, J = 7.2 Hz,
2H), 4.34 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.26 (t, J =
7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 192.70, 165.95,
165.05, 157.74, 155.49, 140.30, 136.75, 135.57, 133.52, 130.76,
130.49, 129.02, 128.33, 127.30, 126.44, 120.22, 62.64, 62.23,
14.04, 13.63. IR (KBr) v: 3065, 2985, 1729, 1673, 1577, 1454,
1371, 1259, 1171, 1110, 1018, 904, 860, 754, 691 cm-1. HRMS
(ESI) m/z calcd for C24H21NO5 [M+H]+: 404.1492. Found:
404.1496.
Scheme 3 The proposed mechanism
4.2.3. dimethyl 2-(4-methylbenzoyl)-6-(p-tolyl)pyridine-3,4-dicar
-boxylate (3c): white solid. Mp: 169-171 0C. 1H NMR (500 MHz,
CDCl3) δ 8.27 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 8.1
Hz, 2H), 7.31 (d, J = 4.1 Hz, 2H), 7.29 (d, J = 4.2 Hz, 2H), 4.00
(s, 3H), 3.87 (s, 3H), 2.46 (s, 3H), 2.42 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 192.29, 166.82, 165.37, 157.71, 155.28, 144.52,
140.92, 139.49, 133.95, 132.99, 131.03, 129.76, 129.05, 127.19,
126.26, 119.86, 53.29, 52.98, 21.82, 21.38. IR (KBr) v: 2953,
1734, 1665, 1584, 1442, 1353, 1276, 1109, 1058, 950, 827, 770,
3. Conclusions
In summary, we have developed a mild reaction to prepare
tetrasubstituted pyridines from α-azidomethyl aryl ketones with
dialkyl but-2-ynedioate. Mild and metal-free reaction conditions
and substituent variation are all notable aspects of this
methodology. Although the scope of asymmetric alkyne reaction
is still limited, these results will initiate further studies towards
an optimization of this new method.
727 cm-1. HRMS (ESI) m/z calcd for C24H21NO5 [M+H]+
404.1492. Found: 404.1489.
:
4.2.4. diethyl 2-(4-methylbenzoyl)-6-(p-tolyl)pyridine-3,4-dica
rboxylate (3d): white solid. Mp: 146-148 0C. 1H NMR (500
MHz, CDCl3) δ 8.22 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.93 (d, J =
8.2 Hz, 2H), 7.30 - 7.27 (m, 4H), 4.46 (q, J = 7.2 Hz, 2H), 4.31
(q, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.42 (s, 3H), 1.43 (t, J = 7.2 Hz,
3H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
192.41, 166.04, 165.24, 157.70, 155.74, 144.46, 140.82, 140.22,
134.07, 133.07, 130.93, 129.72, 129.05, 127.22, 125.89, 119.64,
62.56, 62.13, 21.82, 21.38, 14.04, 13.64. IR (KBr) v: 2983, 1729,
1666, 1579, 1370, 1260, 1177, 1108, 1020, 905, 826, 769, 724
cm-1. HRMS (ESI) m/z calcd for C26H25NO5 [M+H]+ : 432.1805.
Found: 432.1812.
4. Experimental section
4.1 General
Purification of reaction products were carried out by
chromatography using silica gel (200-300mesh). Melting points
were recorded on a BÜCHI B-540 melting point apparatus. NMR
spectra were in CDCl3 or DMSO (1H at 500 MHz and 13C at 125
MHz) and data are reported as follows: chemical shift,
integration, multiplicity ( s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), and coupling constant(s) in Hz. HRMS
data were obtained with using ESI ionization. Infrared spectra
were recorded on FTIR spectrophotometer. Unless otherwise
noted, all reagents were obtained commercially and used without
further purification. The starting material α-azidomethyl aryl
ketones were prepared according to literature methods.1
4.2.5. dimethyl 2-(4-bromobenzoyl)-6-(4-bromophenyl)pyridine-
3,4-dicarboxylate (3e): pale yellow solid. Mp: 185-187 0C 1H
NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H),
7.89 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6
Hz, 2H), 4.02 (s, 3H), 3.91 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 191.33, 166.51, 164.83, 156.58, 154.44, 139.75, 132.35,
131.71, 128.70, 125.49, 120.47, 53.45, 53.15. IR (KBr) v: 2950,
1735, 1672, 1582, 1488, 1441, 1405, 1353, 1273, 1110, 1067,
1009, 949, 906, 883, 773, 736, 687, 637 cm-1. HRMS (ESI) m/z
calcd for C22H15Br2NO5 [M+H]+: 531.9390. Found: 531.9396.
4.2 General procedure for the synthesis of 3
To a 10 ml flask, α-azido ketones (0.5 mmol, 1 equiv.),
dimethyl but-2-ynedioate (0.6 mmol, 1.2 equiv.), K2CO3 (1
mmol, 2 equiv.) and 2 mL acetonitrile was added successively.
The reaction mixture was stirred at 55 ℃ for 12 h. Acetonitrile
was removed by rotary evaporation under reduced pressure. And
then the residue was added 20 mL H2O, extracted with 15 mL
EtOAc twice. The organic layer was wished with 20 mL H2O, 20
mL brine and dried with Na2SO4. And then EtOAc with removed
under reduced pressure, the residue was purified by flash

ACCEPTED MANUSCRIPT
4
Tetrahedron
4.2.6. diethyl 2-(4-bromobenzoyl)-6-(4-bromophenyl)pyridine-
7.5, 2.0Hz, 1H), 7.48 – 7.41 (m, 3H), 7.39 – 7.30 (m, 3H), 4.03
(s, 3H), 4.00 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 193.44,
167.04, 164.27, 157.39, 152.63, 137.42, 136.92, 136.72, 132.87,
132.45, 132.27, 131.69, 131.17, 130.66, 130.31, 130.02, 127.86,
127.22, 126.78, 126.69, 53.40, 53.28. IR (KBr) v: 3088, 2952,
1744, 1680, 1587, 1435, 1358, 1277, 1219, 1153, 1123, 1072,
951, 745, 705, 638 cm-1. HRMS (ESI) m/z calcd for
C22H15Cl2NO5 [M+H]+: 444.0400. Found: 444.0406.
3,4-dicarboxylate (3f): pale yellow solid. Mp: 150-152 0C. 1H
NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H),
7.88 (d, J = 8.6 Hz, 2H), 7.62 - 7.66 (m, 4H) 4.47 (q, J = 7.1 Hz,
2H), 4.35 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.28 (t, J =
7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 191.45, 165.76,
164.69, 156.54, 154.88, 140.46, 135.44, 134.24, 132.30, 132.18,
131.72, 129.01, 128.73, 127.01, 125.40, 120.26, 62.78, 62.36,
14.03, 13.67. IR (KBr) v: 2983, 1728, 1672, 1581, 1402, 1262,
1177, 1107, 1009, 905, 836, 774 cm-1. HRMS (ESI) m/z calcd for
C24H19Br2NO5 [M+H]+: 559.9703. Found: 559.9705.
4.2.12. diethyl 2-(2-chlorobenzoyl)-6-(2-chlorophenyl)pyridine-
3,4-dicarboxylate (3l): colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 8.36 (s, 1H), 7.63 (dd, J =7.3, 2.1 Hz, 1H), 7.50 (dd, J =
7.3, 2.1 Hz, 1H), 7.46 – 7.40 (m, 3H), 7.27-7.36 (m, 3H), 4.43 –
4.52 (m 4H), 1.40 - 1.43 (m, 6H). 13C NMR (125 MHz, CDCl3) δ
193.43, 166.41, 163.97, 157.24, 152.91, 137.96, 136.99, 136.82,
132.86, 132.40, 132.27, 131.65, 131.17, 130.60, 130.29, 130.03,
127.94, 127.19, 126.66, 62.68, 62.37, 14.03, 13.82. IR (KBr) v:
2985, 1737, 1687, 1588, 1438, 1374, 1280, 1167, 1120, 755 cm-1.
HRMS (ESI) m/z calcd for C24H19Cl2NO5 [M+H]+: 472.0713.
Found: 472.0717.
4.2.7. dimethyl 2-(4-methoxybenzoyl)-6-(4-methoxyphenyl)pyridi
-ne-3,4-dicarboxylate (3g): white solid. Mp: 125-127 0C. 1H
NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 8.05 - 8.02 (m, 4H),
7.00 - 6.97 (m, 4H), 4.00 (s, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.87
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.25, 166.91, 165.48,
163.95, 161.68, 157.30, 155.52, 139.48, 133.31, 129.31, 128.80,
128.49, 125.68, 119.20, 114.39, 113.64, 55.53, 55.43, 53.27,
52.96. IR (KBr) v: 3103, 2954, 2839, 1734, 1655, 1595, 1512,
1433, 1357, 1259, 1173, 1110, 946, 835, 773, 719 cm-1. HRMS
(ESI) m/z calcd for C24H21NO7 [M+H]+: 436.1391. Found:
436.1391.
4.2.13. dimethyl 2-(3-methoxybenzoyl)-6-(3-methoxyphenyl)pyrid
-ine-3,4-dicarboxylate (3m): white solid. Mp: 92-94 0C. 1H NMR
(500 MHz, CDCl3) δ 8.30 (s, 1H), 7.64 – 7.62 (m, 3H), 7.56 (d, J
= 7.7 Hz, 1H), 7.40 - 7.37 (m, 2H), 7.18 (dd, J=8, 2.5Hz, 1H),
7.02 (dd, J = 8, 2.5 Hz, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.86 (s,
3H), 3.84 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.26, 166.67,
165.15, 160.23, 159.56, 157.47, 154.82, 139.53, 137.99, 136.77,
130.06, 129.22, 126.89, 124.03, 120.59, 120.31, 119.56, 116.46,
114.50, 112.53, 55.45, 55.35, 53.34, 53.04. IR (KBr) v: 2979,
1732, 1671, 1587, 1458, 1268, 1221, 1099, 1040, 862, 770, 726,
684 cm-1. HRMS (ESI) m/z calcd for C24H21NO7 [M+H]+:
436.1391. Found: 436.1389.
4.2.8. diethyl 2-(4-methoxybenzoyl)-6-(4-methoxyphenyl)pyridine
-3,4-dicarboxylate (3h): colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 8.15 (s, 1H), 8.05 - 8.00 (m, 4H), 6.99 - 6.96 (m, 4H),
4.45 (q, J = 7.1 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H),
3.86 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 191.40, 166.09, 165.34, 163.92,
161.64, 157.32, 155.99, 140.25, 133.16, 129.43, 128.81, 128.61,
125.27, 118.96, 114.36, 113.64, 62.50, 62.06, 55.50, 55.40,
14.03, 13.63. IR (KBr) v: 2892, 2838, 1728, 1661, 1596, 1512,
1461, 1425, 1372, 1258, 1173, 1107, 1027, 905, 840, 775 cm-1.
HRMS (ESI) m/z calcd for C26H25NO7 [M+H]+: 464.1704.
Found: 464.1709.
4.2.14. diethyl 2-(3-methoxybenzoyl)-6-(3-methoxyphenyl)pyridin
-e-3,4-dicarboxylate (3n): colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 8.25 (s, 1H), 7.64 - 7.61 (m, 3H), 7.54 (d, J = 7.7 Hz,
1H), 7.41 – 7.36 (m, 2H), 7.17 (dd, J = 8.0, 2.5Hz, 1H), 7.01 (dd,
J = 8.0, 2.5Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.2 Hz,
2H), 3.86 (s, 3H), 3.84 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.27 (t, J
= 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 192.39, 165.91,
165.02, 160.21, 159.57, 157.47, 155.31, 140.26, 138.14, 136.84,
130.03, 129.25, 126.52, 123.98, 120.38, 120.30, 119.61, 116.33,
114.35, 112.62, 62.63, 62.23, 55.46, 55.36, 14.03, 13.66. IR
(KBr) v: 3018, 2948, 2839, 1730, 1665, 1580, 1490, 1436, 1291,
1224, 1150, 1099, 1043, 955, 878, 768, 728, 668 cm-1. HRMS
(ESI) m/z calcd for C26H25NO9 [M+H]+ :464.1704. Found:
464.1707.
4.2.9. dimethyl 6-(thiophen-2-yl)-2-(thiophene-2-carbonyl)pyridi
-ne-3,4-dicarboxylate (3i): yellow solid. Mp: 143-145 0C. 1H
NMR (500 MHz, CDCl3) δ 8.30 - 8.29 (m, 2H), 7.84 – 7.82 (m,
2H), 7.56 (dd, J = 5.0, 1.0 Hz, 1H), 7.23 - 7.20 (m, 2H), 4.02 (s,
3H), 4.01 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 181.89, 167.30,
164.23, 152.85, 151.90, 142.20, 139.27, 138.39, 137.11, 136.96,
130.03, 128.58, 127.78, 127.74, 127.34, 120.55, 53.39, 53.10. IR
(KBr) v: 3091, 2945, 1737, 1636, 1582, 1435, 1273, 1150, 1094,
745, 691 cm-1. HRMS (ESI) m/z calcd for C18H13NO5S2 [M+H]+:
388.0308. Found: 388.0310.
4.2.15. dimethyl 2-(3,4-dimethoxybenzoyl)-6-(3,4-dimethoxyphen
-yl)pyridine-3,4-dicarboxylate (3o): white solid. Mp: 86-88 C .
4.2.10. diethyl 6-(thiophen-2-yl)-2-(thiophene-2-carbonyl)pyridin
-e-3,4-dicarboxylate (3j): yellow solid. Mp:117-119 0C. 1H NMR
(500 MHz, CDCl3) δ 8.26 (s, 1H), 8.25 (dd, J = 3.9, 1.2 Hz, 1H),
7.84 – 7.80 (m, 2H), 7.55 (dd, J = 5.0, 0.9 Hz, 1H), 7.27 – 7.19
(m, 2H), 4.49 – 4.44 (m, 4H), 1.43 (t, J = 7.1 Hz, 3H), 1.39 (t, J =
7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 182.17, 166.58,
164.05, 152.69, 152.31, 142.31, 139.64, 139.07, 136.92, 136.71,
129.93, 128.54, 127.80, 127.63, 127.23, 120.34, 62.70, 62.16,
14.05, 13.82. IR (KBr) v: 3111, 2982, 1724, 1638, 1581, 1405,
1357, 1277, 1238, 1152, 1095, 1018, 851, 718 cm-1. HRMS (ESI)
m/z calcd for C20H17NO5S2 [M+H]+: 416.0621. Found: 416.0621.
0
1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 7.72 (d, J = 1.9 Hz,
1H), 7.70 – 7.66 (m, 2H), 7.59 (dd, J = 8.4, 1.9 Hz, 1H), 6.97 (d,
J = 8.8 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.00 (s, 3H), 3.97 (s,
3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 191.19, 165.80, 165.54, 157.26,
155.41, 153.85, 151.37, 149.48, 148.94, 139.62, 129.52, 128.59,
126.85, 125.64, 120.36, 119.26, 112.06, 111.16, 110.06, 109.80,
56.12, 56.02, 53.29, 52.96. IR (KBr) v: 3003, 2951, 2838, 1733,
1657, 1587, 1515, 1457, 1423, 1346, 1269, 1153, 1021, 807, 768,
721 cm-1. HRMS (ESI) m/z calcd for C26H25NO9 [M+H]+:
496.1602. Found: 496.1606.
4.2.11. dimethyl 2-(2-chlorobenzoyl)-6-(2-chlorophenyl)pyridine-
3,4-dicarboxylate (3k): colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 8.39 (s, 1H), 7.63 (dd, J = 7.6, 1.3 Hz, 1H), 7.51(dd, J =

ACCEPTED MANUSCRIPT
5
4.2.16. diethyl 2-(3,4-dimethoxybenzoyl)-6-(3,4-dimethoxypheny
Supplementary Material
-l)pyridine-3,4-dicarboxylate (3p): colorless liquid. 1H NMR
(500 MHz, CDCl3) δ 8.15 (s, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.68
– 7.65 (m, 2H), 7.54 (dd, J = 8.4, 1.9 Hz, 1H), 6.96 (d, J = 8.2
Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.29
(q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.94 (s, 3H), 3.91
(s, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 191.37, 166.01, 165.41, 157.28,
155.83, 153.80, 151.30, 149.44, 148.95, 140.34, 129.64, 128.68,
126.78, 125.25, 120.37, 119.07, 111.85, 111.13, 110.12, 109.82,
62.56, 62.10, 56.10, 56.03, 56.01, 14.02, 13.67. IR (KBr) v:
3083, 2974, 2840, 1729, 1662, 1591, 1518, 1460, 1425, 1378,
1343, 1268, 1175, 1146, 1106, 1017, 861, 768, 721 cm-1. HRMS
(ESI) m/z calcd for C28H29NO9 [M+H]+: 524.1915. Found:
524.1916.
Copies of NMR spectra for all products and single-crystal X-
ray diffraction analysis of 3i.
References and notes
1. P. Fu, S. X. Wang, K. Hong, P. P. Liu, Y. Wang, W. M. Zhu,
J. Nat. Prod. 2011, 74, 1751.
2. a) Y. L. Chen, J. Braselton, J. Forman, R. J. Gallaschun, R.
Mansbach, A. W. Schmidt, T. F. Seeger, J. S. Sprouse, F. D.
Tingley, E. Winston, D. W. Schulz, J. Med. Chem. 2008, 51,
1377; b) Y. Miyamoto, Y. Banno, T. Yamashita, T. Fujimoto,
S.
4.2.17. dimethyl 2-(4-chlorobenzoyl)-6-(4-chlorophenyl)pyridine
Oi, Y. Moritoch, T. Askawa, O. Kataoka, H. Yashiro, K.
Takeuchi, N. Suzuki, K. Ikedo, T. Kosaka, S. Tsubotani, A.
Tani, M. Sasaki, M. Funami, M. Amano, Y. Yamamoto, K.
Aertgeerts, J. Yano, H. Maezaki, J.Med. Chem. 2011, 54, 831;
c) M. C. Bagley, J. W. Dale, E. A. Merritt, X. Xiong, Chem.
Rev. 2005, 105, 685.
3. F. Durola, J. P. Sauvage, O. S. Wenger, Chem. Commun. 2006,
171.
4. Z. Ren, Z. Zhang, B. Yang, Y. Wang, Z. Guan, Org. Lett.
2011, 13, 5394.
0
1
-3,4-dicarboxylate (3q): pale yellow solid. Mp:171-173 C. H
NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 8.00 – 7.96 (m, 4H),
7.49 – 7.46 (m, 4H), 4.02 (s, 3H), 3.91 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 191.15, 166.52, 164.85, 156.49, 154.48, 140.22,
139.72, 137.05, 134.87, 133.76, 132.21, 129.37, 128.73, 128.48,
127.29, 120.48, 53.45, 53.15. IR (KBr) v: 3092, 2951, 1735,
1672, 1585, 1492, 1441, 1411, 1410, 1354, 1270, 1169, 1104,
1013, 951, 836, 773 cm-1. HRMS (ESI) m/z calcd for
C22H15Cl2NO5 [M+H]+: 444.0400. Found: 444.0409.
5. P. Too, T. Noji, Y. Lim, X. Li, S. Chiba, Synlett. 2011, 19,
2789.
6. a) C. Yan, X. Cai, Q. Fang, T. Wang, M. Zheng, Org. Biomol.
Chem. 2007, 5, 945; b) B. Jiang, W. Hao, X. Wang, F. Shi, S.
Tu, J. Comb. Chem. 2009, 11, 846.
4.2.18. diethyl 2-(4-chlorobenzoyl)-6-(4-chlorophenyl)pyridine-
0
1
3,4-dicarboxylate (3r): pale yellow solid. Mp: 132-134 C. H
NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 8.00 – 7.95 (m, 4H),
7.51 – 7.45 (m, 4H), 4.47 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz,
2H), 1.44 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 191.28, 165.77, 164.72, 156.47, 154.93,
140.45, 140.18, 136.96, 134.99, 133.83, 132.11, 129.33, 128.74,
128.51, 126.95, 120.26, 62.78, 62.35, 14.04, 13.67. IR (KBr) v:
3088, 2984, 1729, 1671, 1583, 1405, 1370, 1262, 1177, 1103,
1013, 838, 775 cm-1. HRMS (ESI) m/z calcd for C24H19Cl2NO5
[M+H]+: 472.0713. Found: 472.0719.
7. S. Kantevari, S. Patpi, D. Addla, S. Putapatri, B. Sridhar, P.
Yogeeswari, D. Sriram, ACS Comb. Sci. 2011, 13, 427.
8. S. Liu, L. Liebeskind, J. Am. Chem. Soc. 2008, 130, 6918.
9. a) B. Ranu, R. Jana, S. Sowmiah, J. Org .Chem. 2007, 72,
3152; b) Y. Sainz, S. Raw, R. J. K. Taylor, J. Org .Chem.
2005, 70, 10086; c) M. N. Khan, S. Pal, T. Parvin, L. H.
Choudhury, RSC Adv. 2012, 2, 12305; d) J. Shao, W. Yu, Z.
Shao, Y. Yu, Chem. Commun. 2012, 48, 2785.
10. a) B. Batanero, J. Escudero, F. Barba, Org. Lett. 1999, 1,
1521; b) I. Freifeld, H. Shojaei, P. Langer, J. Org. Chem.
2006, 71, 4965; c) T. Patonayl, R. V. Hoffman, J. Org. Chem.
1995, 60, 2368; d) R. F. Klima, A. V. Jadhav, P. N. D. Singh,
M. Chang, C. Vanosn, J. Sankaranarayana, M. Vu, N.
Ibrahim, E. Ross, S. McCloskey, R. S. Murthy, J. A. Krause,
B. S. Ault, A. D. Gudmundsdóttir, J. Org. Chem. 2007, 72,
6372; e) C. H. Chou, L. T. Chu, I. Y. Chen, B. J. Wu,
Heterocycles. 2008, 75, 577; f) P. Langer, I. Freifeld, Chem.
Commun. 2002, 0, 2668.
4.2.19. dimethyl 2-(4-nitrobenzoyl)-6-(4-nitrophenyl)pyridine-
0
1
3,4-dicarboxylate (3s): yellow solid. Mp: 70-72 C . H NMR
(500 MHz, CDCl3) δ 8.49 (s, 1H), 8.38 – 8.34 (m, 4H), 8.20 –
8.16 (m, 4H), 4.05 (s, 3H), 3.96 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 190.48, 166.12, 164.17, 155.30, 153.56, 150.51,
149.15, 141.77, 140.13, 140.00, 131.68, 128.96, 128.10, 124.37,
123.52, 122.24, 53.70, 53.40. IR (KBr) v: 1730, 1636, 1596,
1514, 1397, 1342, 1109, 844, 738, 687 cm-1. HRMS (ESI) m/z
calcd for C22H15N3O9 [M+H]+: 466.0881. Found: 466.0877.
Acknowledgments
We gratefully acknowledge The Project of Science
Technology Department of Zhejiang Province (2012C33065) and
Project of Education Department of Zhejiang Province
(Y201223193) for their financial support. Mr Jianming Gu of the
X-ray crystallography facility of Zhejiang University is
acknowledged for the assistance on crystal structural analysis.
We also thank Jianyang Pan (Pharmaceutical Informatics
Institute, Zhejiang University) for performing NMR spectrometry
for structure elucidation.
11. (a) J. Chen, W. Chen, Y. Yu, G. Zhang, Tetrahedron Lett.
2013, 54, 1572. (b) J. H. Oyer, D. Straw, J. Am. Chem. Soc.
1952, 74, 4506-4508.
12. a) P. Wu, A. K. Feldman, A. K. Nugent, C. J. Harker, A.
Scheel, B. B. Voit, J. Pyun, J. M. J. Fréchet, K. B. Sharpless,
V. V. Fokin, Angew. Chem. Int. Ed., 2004, 43, 3928; b) V. V.
Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. Int. Ed. 2002, 41, 2596.
13. P. Shanmugavelan, S. Nagarajan, M. Sathishkumar, A.
Ponnuswamy, P. Yogeeswari, D. Sriram, Bioorg. Med. Chem.
Lett. 2011, 21, 7273.

ACCEPTED MANUSCRIPT
6
Tetrahedron
14. Y. Li, D. Hong, P. Lu, Y. Wang, Tetrahedron Lett. 2011, 52,
4161.

ACCEPTED MANUSCRIPT
Supporting information
General Information:
Purification of reaction products were carried out by chromatography using silica gel (200-300mesh). Melting points were
recorded on a BÜCHI B-540 melting point apparatus. NMR spectra were in CDCl3 or DMSO (1H at 500 MHz and 13C at 125
MHz) and data are reported as follows: chemical shift, integration, multiplicity ( s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), and coupling constant(s) in Hz. Infrared spectra were recorded on FTIR spectrophotometer. HRMS data were
obtained with using ESI ionization. Unless otherwise noted, all reagents were obtained commercially and used without further
purification. The starting material α-azido ketones were prepared according to literature methods.1
General Procedure for the Synthesis of 3a-3s
To a 10 ml flask, α-azido ketones (0.5 mmol, 1 equiv.), dimethyl but-2-ynedioate (0.6 mmol, 1.2 equiv.), K2CO3 (1 mmol, 2
equiv.) and 2 mL acetonitrile was added successively. The reaction mixture was stirred at 55 ℃ for 12 h. Acetonitrile was
removed by rotary evaporation under reduced pressure. And then the residue was added 20 mL H2O, extracted with 15 mL
EtOAc twice. The organic layer was wished with 20 mL H2O, 20 mL brine and dried with Na2SO4. And then EtOAc with
removed under reduced pressure, the residue was purified by flash chromatography (Petroleum ether/EtOAc) on slica gel to
afford 3a-3s.

ACCEPTED MANUSCRIPT
Characterization Data:
dimethyl 2-benzoyl-6-phenylpyridine-3,4-dicarboxylate (3a): white solid, Mp: 123-125 0C. 1H NMR (500 MHz, CDCl3) δ
8.31 (s, 1H), 8.06 (dd, J = 6.7, 3.0 Hz, 2H), 8.01 (dd, J=6.7, 3.0 Hz 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.52 – 7.47 (m, 5H), 4.00 (s,
3H), 3.88 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.58, 166.74, 165.17, 157.73, 154.98, 139.54, 136.62, 135.50, 133.54,
130.87, 130.57, 129.06, 128.32, 127.28, 126.84, 120.45, 53.36, 53.06. IR (KBr) v: 2952, 1732, 1676, 1584, 1444, 1358 1261,
1100, 950, 804, 759, 691 cm-1. HRMS (ESI) m/z calcd for C22H17NO5 [M+H]+ :376.1179. Found:376.1182.
diethyl 2-benzoyl-6-phenylpyridine-3,4-dicarboxylate (3b): white solid. Mp: 87-89 0C. 1H NMR (500 MHz, CDCl3) δ 8.28
(s, 1H), 8.07 (dd, J = 6.5, 3.3 Hz, 2H), 8.03 (dd, J = 8.3, 1.1 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.53 – 7.47 (m, 5H), 4.47 (q, J
= 7.2 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
192.70, 165.95, 165.05, 157.74, 155.49, 140.30, 136.75, 135.57, 133.52, 130.76, 130.49, 129.02, 128.33, 127.30, 126.44,
120.22, 62.64, 62.23, 14.04, 13.63. IR (KBr) v: 3065, 2985, 1729, 1673, 1577, 1454, 1371, 1259, 1171, 1110, 1018, 904, 860, 754,
691 cm-1. HRMS (ESI) m/z calcd for C24H21NO5 [M+H]+ :404.1492. Found: 404.1496.
0
1
dimethyl 2-(4-methylbenzoyl)-6-(p-tolyl)pyridine-3,4-dicarboxylate (3c): white solid. Mp: 169-171 C. H NMR (500
MHz, CDCl3) δ 8.27 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 4.1 Hz, 2H), 7.29 (d, J = 4.2 Hz,
2H), 4.00 (s, 3H), 3.87 (s, 3H), 2.46 (s, 3H), 2.42 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.29, 166.82, 165.37, 157.71,
155.28, 144.52, 140.92, 139.49, 133.95, 132.99, 131.03, 129.76, 129.05, 127.19, 126.26, 119.86, 53.29, 52.98, 21.82, 21.38.
IR (KBr) v: 2953, 1734, 1665, 1584, 1442, 1353, 1276, 1109, 1058, 950, 827, 770, 727 cm-1. HRMS (ESI) m/z calcd for
C24H21NO5 [M+H]+ :404.1492. Found: 404.1489.

ACCEPTED MANUSCRIPT
diethyl 2-(4-methylbenzoyl)-6-(p-tolyl)pyridine-3,4-dicarboxylate (3d): white solid. Mp: 146-148 0C. 1H NMR (500 MHz,
CDCl3) δ 8.22 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.30 - 7.27 (m, 4H), 4.46 (q, J = 7.2 Hz, 2H), 4.31
(q, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.42 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3)
δ 192.41, 166.04, 165.24, 157.70, 155.74, 144.46, 140.82, 140.22, 134.07, 133.07, 130.93, 129.72, 129.05, 127.22, 125.89,
119.64, 62.56, 62.13, 21.82, 21.38, 14.04, 13.64. IR (KBr) v: 2983, 1729, 1666, 1579, 1370, 1260, 1177, 1108, 1020, 905,
826, 769, 724 cm-1. HRMS (ESI) m/z calcd for C26H25NO5 [M+H]+ : 432.1805. Found: 432.1812.
dimethyl 2-(4-bromobenzoyl)-6-(4-bromophenyl)pyridine-3,4-dicarboxylate (3e): pale yellow solid. Mp: 185 - 187 0C 1H
NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.64 (d,
J = 8.6 Hz, 2H), 4.02 (s, 3H), 3.91 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.33, 166.51, 164.83, 156.58, 154.44, 139.75,
132.35, 131.71, 128.70, 125.49, 120.47, 53.45, 53.15. IR (KBr) v: 2950, 1735, 1672, 1582, 1488, 1441, 1405, 1353, 1273, 1110,
1067, 1009, 949, 906, 883, 773, 736, 687, 637 cm-1. HRMS (ESI) m/z calcd for C22H15Br2NO5 [M+H]+ : 531.9390. Found:
531.9396.
0
1
diethyl 2-(4-bromobenzoyl)-6-(4-bromophenyl)pyridine-3,4-dicarboxylate(3f): pale yellow solid. Mp: 150-152 C. H
NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 7.62 - 7.66 (m, 4H) 4.47 (q, J =
7.1 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 191.45,
165.76, 164.69, 156.54, 154.88, 140.46, 135.44, 134.24, 132.30, 132.18, 131.72, 129.01, 128.73, 127.01, 125.40, 120.26,
62.78, 62.36, 14.03, 13.67. IR (KBr) v: 2983, 1728, 1672, 1581, 1402, 1262, 1177, 1107, 1009, 905, 836, 774 cm-1. HRMS
(ESI) m/z calcd for C24H19Br2NO5 [M+H]+ : 559.9703. Found:559.9705.

ACCEPTED MANUSCRIPT
0
1
dimethyl 2-(4-methoxybenzoyl)-6-(4-methoxyphenyl)pyridine-3,4-dicarboxylate (3g): white solid. Mp: 125-127 C. H
NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 8.05 - 8.02 (m, 4H), 7.00 - 6.97 (m, 4H), 4.00 (s, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.87
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.25, 166.91, 165.48, 163.95, 161.68, 157.30, 155.52, 139.48, 133.31, 129.31,
128.80, 128.49, 125.68, 119.20, 114.39, 113.64, 55.53, 55.43, 53.27, 52.96. IR (KBr) v: 3103, 2954, 2839, 1734, 1655, 1595,
1512, 1433, 1357, 1259, 1173, 1110, 946, 835, 773, 719 cm-1. HRMS (ESI) m/z calcd for C24H21NO7 [M+H]+ :436.1391.
Found: 436.1391.
diethyl 2-(4-methoxybenzoyl)-6-(4-methoxyphenyl)pyridine-3,4-dicarboxylate(3h): colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 8.15 (s, 1H), 8.05 - 8.00 (m, 4H), 6.99 - 6.96 (m, 4H), 4.45 (q, J = 7.1 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 3.90 (s,
3H), 3.86 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 191.40, 166.09, 165.34,
163.92, 161.64, 157.32, 155.99, 140.25, 133.16, 129.43, 128.81, 128.61, 125.27, 118.96, 114.36, 113.64, 62.50, 62.06, 55.50,
55.40, 14.03, 13.63. IR (KBr) v: 2892, 2838, 1728, 1661, 1596, 1512, 1461, 1425, 1372, 1258, 1173, 1107, 1027, 905, 840, 775
cm-1. HRMS (ESI) m/z calcd for C26H25NO7 [M+H]+ :464.1704. Found:464.1709.
0
1
dimethyl 6-(thiophen-2-yl)-2-(thiophene-2-carbonyl)pyridine-3,4-dicarboxylate (3i): yellow solid. Mp: 143-145 C. H
NMR (500 MHz, CDCl3) δ 8.30 - 8.29 (m, 2H), 7.84 – 7.82 (m, 2H), 7.56 (dd, J = 5.0, 1.0 Hz, 1H), 7.23 - 7.20 (m, 2H), 4.02
(s, 3H), 4.01 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 181.89, 167.30, 164.23, 152.85, 151.90, 142.20, 139.27, 138.39, 137.11,
136.96, 130.03, 128.58, 127.78, 127.74, 127.34, 120.55, 53.39, 53.10. IR (KBr) v: 3091, 2945, 1737, 1636, 1582, 1435, 1273,
1150, 1094, 745, 691 cm-1. HRMS (ESI) m/z calcd for C18H13NO5S2 [M+H]+ :388.0308. Found: 388.0310.

ACCEPTED MANUSCRIPT
0
1
diethyl 6-(thiophen-2-yl)-2-(thiophene-2-carbonyl)pyridine-3,4-dicarboxylate (3j): yellow solid. Mp:117-119 C. H
NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 8.25 (dd, J = 3.9, 1.2 Hz, 1H), 7.84 – 7.80 (m, 2H), 7.55 (dd, J = 5.0, 0.9 Hz, 1H),
7.27 – 7.19 (m, 2H), 4.49 – 4.44 (m, 4H), 1.43 (t, J = 7.1 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
182.17, 166.58, 164.05, 152.69, 152.31, 142.31, 139.64, 139.07, 136.92, 136.71, 129.93, 128.54, 127.80, 127.63, 127.23,
120.34, 62.70, 62.16, 14.05, 13.82. IR (KBr) v: 3111, 2982, 1724, 1638, 1581, 1405, 1357, 1277, 1238, 1152, 1095, 1018,
851, 718 cm-1. HRMS (ESI) m/z calcd for C20H17NO5S2 [M+H]+ : 416.0621. Found: 416.0621.
1
dimethyl 2-(2-chlorobenzoyl)-6-(2-chlorophenyl)pyridine-3,4-dicarboxylate (3k): colorless liquid. H NMR (500 MHz,
CDCl3) δ 8.39 (s, 1H), 7.63 (dd, J = 7.6, 1.3 Hz, 1H), 7.51(dd, J = 7.5, 2.0Hz, 1H), 7.48 – 7.41 (m, 3H), 7.39 – 7.30 (m, 3H),
4.03 (s, 3H), 4.00 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 193.44, 167.04, 164.27, 157.39, 152.63, 137.42, 136.92, 136.72,
132.87, 132.45, 132.27, 131.69, 131.17, 130.66, 130.31, 130.02, 127.86, 127.22, 126.78, 126.69, 53.40, 53.28. IR (KBr) v:
3088, 2952, 1744, 1680, 1587, 1435, 1358, 1277, 1219, 1153, 1123, 1072, 951, 745, 705, 638 cm-1. HRMS (ESI) m/z calcd
for C22H15Cl2NO5 [M+H]+ : 444.0400. Found: 444.0406.
1
diethyl 2-(2-chlorobenzoyl)-6-(2-chlorophenyl)pyridine-3,4-dicarboxylate (3l): colorless liquid. H NMR (500 MHz,
CDCl3) δ 8.36 (s, 1H), 7.63 (dd, J =7.3, 2.1 Hz, 1H), 7.50 (dd, J = 7.3, 2.1 Hz, 1H), 7.46 – 7.40 (m, 3H), 7.27-7.36 (m, 3H),
4.43 – 4.52 (m 4H), 1.40 - 1.43 (m, 6H). 13C NMR (125 MHz, CDCl3) δ 193.43, 166.41, 163.97, 157.24, 152.91, 137.96,
136.99, 136.82, 132.86, 132.40, 132.27, 131.65, 131.17, 130.60, 130.29, 130.03, 127.94, 127.19, 126.66, 62.68, 62.37, 14.03,
13.82. IR (KBr) v: 2985, 1737, 1687, 1588, 1438, 1374, 1280, 1167, 1120, 755 cm-1. HRMS (ESI) m/z calcd for C24H19Cl2NO5
[M+H]+ : 472.0713. Found : 472.0717.

ACCEPTED MANUSCRIPT
0
1
dimethyl 2-(3-methoxybenzoyl)-6-(3-methoxyphenyl)pyridine-3,4-dicarboxylate (3m): white solid. Mp: 92-94 C. H
NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.64 – 7.62 (m, 3H), 7.56 (d, J = 7.7 Hz, 1H), 7.40 - 7.37 (m, 2H), 7.18 (dd, J=8,
2.5Hz, 1H), 7.02 (dd, J = 8, 2.5 Hz, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
192.26, 166.67, 165.15, 160.23, 159.56, 157.47, 154.82, 139.53, 137.99, 136.77, 130.06, 129.22, 126.89, 124.03, 120.59,
120.31, 119.56, 116.46, 114.50, 112.53, 55.45, 55.35, 53.34, 53.04. IR (KBr) v: 2979, 1732, 1671, 1587, 1458, 1268, 1221,
1099, 1040, 862, 770, 726, 684 cm-1. HRMS (ESI) m/z calcd for C24H21NO7 [M+H]+ :436.1391. Found: 436.1389.
diethyl 2-(3-methoxybenzoyl)-6-(3-methoxyphenyl)pyridine-3,4-dicarboxylate (3n): colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 8.25 (s, 1H), 7.64 - 7.61 (m, 3H), 7.54 (d, J = 7.7 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.17 (dd, J = 8.0, 2.5Hz, 1H), 7.01
(dd, J = 8.0, 2.5Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 192.39, 165.91, 165.02, 160.21, 159.57, 157.47, 155.31, 140.26, 138.14, 136.84, 130.03,
129.25, 126.52, 123.98, 120.38, 120.30, 119.61, 116.33, 114.35, 112.62, 62.63, 62.23, 55.46, 55.36, 14.03, 13.66. IR (KBr)
v: 3018, 2948, 2839, 1730, 1665, 1580, 1490, 1436, 1291, 1224, 1150, 1099, 1043, 955, 878, 768, 728, 668 cm-1. HRMS
(ESI) m/z calcd for C26H25NO9 [M+H]+ :464.1704. Found: 464.1707.
dimethyl 2-(3,4-dimethoxybenzoyl)-6-(3,4-dimethoxyphenyl)pyridine-3,4-dicarboxylate (3o): white solid. Mp: 86-88 0C .
1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.70 – 7.66 (m, 2H), 7.59 (dd, J = 8.4, 1.9 Hz, 1H), 6.97
(d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 191.19, 165.80, 165.54, 157.26, 155.41, 153.85, 151.37, 149.48, 148.94, 139.62, 129.52,
128.59, 126.85, 125.64, 120.36, 119.26, 112.06, 111.16, 110.06, 109.80, 56.12, 56.02, 53.29, 52.96. IR (KBr) v: 3003, 2951,
2838, 1733, 1657, 1587, 1515, 1457, 1423, 1346, 1269, 1153, 1021, 807, 768, 721 cm-1. HRMS (ESI) m/z calcd for C26H25NO9
[M+H]+ : 496.1602. Found: 496.1606.

ACCEPTED MANUSCRIPT
1
diethyl 2-(3,4-dimethoxybenzoyl)-6-(3,4-dimethoxyphenyl)pyridine-3,4-dicarboxylate (3p): colorless liquid. H NMR
(500 MHz, CDCl3) δ 8.15 (s, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.68 – 7.65 (m, 2H), 7.54 (dd, J = 8.4, 1.9 Hz, 1H), 6.96 (d, J =
8.2 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.94 (s,
3H), 3.91 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 191.37, 166.01, 165.41,
157.28, 155.83, 153.80, 151.30, 149.44, 148.95, 140.34, 129.64, 128.68, 126.78, 125.25, 120.37, 119.07, 111.85, 111.13,
110.12, 109.82, 62.56, 62.10, 56.10, 56.03, 56.01, 14.02, 13.67. IR (KBr) v: 3083, 2974, 2840, 1729, 1662, 1591, 1518, 1460,
1425, 1378, 1343, 1268, 1175, 1146, 1106, 1017, 861, 768, 721 cm-1. HRMS (ESI) m/z calcd for C28H29NO9 [M+H]+ :
524.1915. Found: 524.1916.
dimethyl 2-(4-chlorobenzoyl)-6-(4-chlorophenyl)pyridine-3,4-dicarboxylate (3q): pale yellow solid. Mp:171-173 0C. 1H
NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 8.00 – 7.96 (m, 4H), 7.49 – 7.46 (m, 4H), 4.02 (s, 3H), 3.91 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 191.15, 166.52, 164.85, 156.49, 154.48, 140.22, 139.72, 137.05, 134.87, 133.76, 132.21, 129.37, 128.73,
128.48, 127.29, 120.48, 53.45, 53.15. IR (KBr) v: 3092, 2951, 1735, 1672, 1585, 1492, 1441, 1411, 1410, 1354, 1270, 1169,
1104, 1013, 951, 836, 773 cm-1. HRMS (ESI) m/z calcd for C22H15Cl2NO5 [M+H]+ : 444.0400. Found: 444.0409.
0
1
diethyl 2-(4-chlorobenzoyl)-6-(4-chlorophenyl)pyridine-3,4-dicarboxylate (3r): pale yellow solid. Mp: 132-134 C. H
NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 8.00 – 7.95 (m, 4H), 7.51 – 7.45 (m, 4H), 4.47 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2
Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 191.28, 165.77, 164.72, 156.47,
154.93, 140.45, 140.18, 136.96, 134.99, 133.83, 132.11, 129.33, 128.74, 128.51, 126.95, 120.26, 62.78, 62.35, 14.04, 13.67.
IR (KBr) v: 3088, 2984, 1729, 1671, 1583, 1405, 1370, 1262, 1177, 1103, 1013, 838, 775 cm-1. HRMS (ESI) m/z calcd for
C24H19Cl2NO5 [M+H]+ :472.0713. Found: 472.0719.

ACCEPTED MANUSCRIPT
dimethyl 2-(4-nitrobenzoyl)-6-(4-nitrophenyl)pyridine-3,4-dicarboxylate (3s): yellow solid. Mp: 70-72 0C . 1H NMR (500
MHz, CDCl3) δ 8.49 (s, 1H), 8.38 – 8.34 (m, 4H), 8.20 – 8.16 (m, 4H), 4.05 (s, 3H), 3.96 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 190.48, 166.12, 164.17, 155.30, 153.56, 150.51, 149.15, 141.77, 140.13, 140.00, 131.68, 128.96, 128.10, 124.37, 123.52,
122.24, 53.70, 53.40. IR (KBr) v: 1730, 1636, 1596, 1514, 1397, 1342, 1109, 844, 738, 687 cm-1. HRMS (ESI) m/z calcd for
C22H15N3O9 [M+H]+ : 466.0881. Found: 466.0877.

ACCEPTED MANUSCRIPT
1H NMR and 13C NMR spectra：

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT