Access to 4,6-Diarylpicolinates via a Domino Reaction of Cyclic Sulfamidate Imines with Morita-Baylis-Hillman Acetates of Nitroolefins/Nitrodienes

Article abstract of DOI:10.1021/acs.joc.6b00472

An interesting domino reaction of 5-membered cyclic sulfamidate imines with a variety of Morita-Baylis-Hillman acetates of nitroolefins/nitrodienes in the presence of DABCO as an organic base at 55 °C is reported for the first time. This new synthetic strategy provides a series of pharmacologically interesting 4,6-diarylpicolinates in high to excellent yields and allows several compatible functionalities on aryl rings. Moreover, the biologically interesting imidazo[1,2-a]pyridine (alpidem derivative) has been prepared in high chemical yield through a unique procedure.

Full text of DOI:10.1021/acs.joc.6b00472

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Note
Access to 4,6-Diarylpicolinates via a Domino Reaction of Cyclic Sulfamidate
Imines with Morita-Baylis-Hillman Acetates of Nitroolefins/Nitrodienes
Debashis Majee, Soumen Biswas, Shaikh M. Mobin, and Sampak Samanta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00472 • Publication Date (Web): 29 Apr 2016
Downloaded from http://pubs.acs.org on May 5, 2016
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Access to 4,6-Diarylpicolinates via a Domino Reaction of Cyclic Sulfamidate
Imines with Morita-Baylis-Hillman Acetates of Nitroolefins/Nitrodienes
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Debashis Majee, Soumen Biswas, Shaikh M. Mobin and Sampak Samanta*
Discipline of Chemistry, Indian Institute of Technology Indore, Simrol, Indore, 452020,
Madhya Pradesh, India.
*Corresponding author. Tel +91ꢀ731ꢀ2438753
Email: sampaks@iiti.ac.in
ABSTRACT: An interesting domino reaction of 5ꢀmembered cyclic sulfamidate imines with a
variety of MoritaꢀBaylisꢀHillman acetates of nitroolefines/nitrodienes in the presence of
DABCO as an organic base at 55 ºC is reported for the first time. This new synthetic strategy
provides a series of pharmacologically interesting 4,6ꢀdiarypicolinates in high to excellent yields
and allows several compatible functionalities on aryl rings. Moreover, the biologically
interesting imidazo[1,2ꢀa]pyridine (Alpidem derivative) has been prepared in high chemical
yield through a unique procedure.
KEYWORDS: picolinate derivative, imidazo[1,2ꢀa]pyridine, cyclic sulfamidate imine, MBH
acetate of nitroolefin, metalꢀfree, domino reaction, anxiolytic drug
Design and development of an innovative approach towards the rapid access to
important functionalized pyridine frameworks through oneꢀpot operation is unanimously
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one of the most active research areas in synthetic and medicinal chemistry because this
popular heterocyclic core has been largely found in a variety of biologically active natural
molecules.1 Moreover, substituted pyridines have shown versatile applications in almost
all branches of chemical science such as active pharmaceutical research,1,2 functional
materials,3 agrochemicals,4 polymer,5 coordination chemistry,6 catalysis7 etc. Owing to
their broad spectrum of applications, huge efforts have been devoted for the syntheses of
a wide range of functionalized pyridine scaffolds by adopting several classical and
modern techniques such as condensation reactions of ketones with amines, multiꢀ
component reactions, cycloaddition reactions, transition metalꢀsalt catalyzed CꢀH bond
functionalization etc.8 Despite the rich history on pyridine syntheses, the access to
functionalized picolinic acid derivative (carboxylic acid at Cꢀ2 position on pyridine ring)
has seen little attention (Scheme 1) despite their proven biological and pharmaceutical
importance.9, 1dꢀe For example, Rovis et al.9b has synthesized a novel picolinate derivative
through a regioselective coupling reaction between α,βꢀunsaturated Oꢀpivaloyl oxime and
ethyl acrylate at 85 °C using Rhꢀsalt/AgOAc as the combined catalytic system (Scheme
1a). In 2015, CAN/pyrrolidine mediated tandem threeꢀcomponent annulation reaction for
the access to functionalized picolinates involving β,γꢀunsaturated αꢀketoester, ketones and
ammonium acetate has been nicely described by Zhu and coꢀworkers (Scheme 1b).9c
Furthermore, MoritaꢀBaylisꢀHillman (MBH) acetates of methyl vinyl ketone as
bielectrophiles has been utilized in the twoꢀstep reaction with sodium diethyl oxaloacetate
and ammonium acetate for the construction of pyridine derivatives as reported by Kim et
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al 9d
.
(Scheme 1c). However, most of the above techniques suffer from one or more
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practical difficulties such as use of expensive metalꢀsalts, limited substrate scope, poor
chemical yields with multiple side products, harsh reaction conditions etc.
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Scheme 1.Various approaches for the syntheses of picolinate derivatives.
Therefore, the development of a simple and efficient new synthetic tactic for the rapid
construction of multiꢀfunctionalized picolinate frameworks under metalꢀfree conditions is
always challenging task in the context of both academic and industrial standpoints of
view.
Recently, we found that 5ꢀmembered cyclic sulfamidate imines could act as potential
nucleophiles while reacting with several arylꢀaldehydes/α,βꢀunsaturated aldehydes.10 On
the other hand, MBH acetates of nitroolefins have been extensively used as suitable 1,3ꢀ
bielectrophiles in the SN2' additionꢀelimination sequence reaction with several
nucleophiles, constructing a variety of 5/6ꢀmembered heterocycles.11 With this
understanding, we thought that cyclic sulfamidate imines may also attack MBH acetates
of nitroolefins in the SN2ˊꢀaddition manner using a base (Scheme 2). To verify this
synthetic plan, we began the model reaction involving 4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazoleꢀ
2,2ꢀdoxide (1a) and MBH acetate 2a in THF at room temperature using a 50 mol% 1,4ꢀ
diazabicyclo[2.2.2]octane (DABCO) as an organobase. After 20 h, surprisingly, we
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isolated ethyl 4,6ꢀdiphenylpicolinate (3aa
)
in 32% yield instead of addition adduct 4.
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The product 3aa was carefully characterized by its spectroscopic data.
O
O
S
N
O
CO2Et
expected
SN2 -addition attack
Ph
9
OAc
CO2Et
O
O
N
NO2
4
not observed
Ph
Ph
S
O2N
+
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O
DABCO (0.5 equiv)
THF, rt, 20 h
Ph
2a
Ph
1a
isolated
Ph
N
3aa
CO2Et
(32% yield)
Scheme 2. DABCO mediated domino reaction between 1a with 2a.
The above fascinating result as well as our continued interest in the development of a new
synthetic method for the synthesis of Nꢀheterocycles including pyridine derivatives under metalꢀ
free conditions,12 here in we report a unique and general synthetic strategy for the rapid access to
previously unknown functionalized 4,6ꢀdiarylꢀsubstituted picolinates in high to excellent yields
via a domino reaction of a series of 4ꢀarylꢀsubstituted cyclic sulfamidate imines with MBH
acetates of nitroalkenes/nitrodienes as 1,3ꢀbielectrophiles in the presence of DABCO as an
inexpensive base under mild conditions (Scheme 1d).
In view of the above interesting results, we further examined this domino reaction in order to
improve the chemical yield of 3aa. Thus, on increasing the amount of DABCO from 0.5 equiv.
to 1.5 equiv., yield of 3aa was dramatically improved from 32% to 84% (entries 2 and 3, Table
1) after 10ꢀ12 h. Interestingly, excellent yields (87ꢀ92%, entries 4 and 5) of 3aa were
obtained within short time spans (3ꢀ6 h) when the reaction was performed
Table 1. Optimization reaction conditionsa
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Ph
OAc
CO2Et
O
O
N
S
O2N
Conditions
O
+
Ph
N
3aa
CO2Et
Ph
2a
Ph
1a
6
7
8
9
entry
1c
2d
3
catalyst
solvent
THF
temp (°C)
rt
time (h)
yield (%)b
32
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
20
14
10
6
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THF
rt
62
THF
rt
84
4
THF
45
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87
5
THF
3
92
6
toluene
CH2Cl2
MeCN
EtOAc
DMSO
DMF
EtOH
THF
3
86
7
3
80
8
3
79
9
3
84
10
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5
48
5
40
5
58
6
12
DMAP
THF
6
18
C5H5N
THF
6
30
DIPEA
Et3N
THF
6
11
THF
6
42
THF
6
50
(
quinine)
aUnless otherwise noted, all the reactions were performed with 1a (0.2 mmol), 2a (0.22
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mmol) and DABCO (0.3 mmol, 1.5 equiv) in specified solvents 0.5 mL and temperatures.
bIsolated yield . c0.5 equiv. of DABCO. d1.0 equiv. of DABCO.
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at heating conditions (45 to 55°C). For this catalyst, screening of organic solvents
revealed that nonꢀpolar solvents like toluene, CH2Cl2, MeCN and EtOAc produced better
yields (79ꢀ86%, entries 6ꢀ9) as compared to polar ones (DMSO, DMF and EtOH, 40ꢀ58%
yields, entries 10ꢀ12) under identical conditions. Considering the yield of 3aa (92%, entry
5), THF was chosen as the best solvent for this reaction. Next, we investigated the
influence of several common organic bases namely DBU, DMAP, DIPEA, pyridine,
triethylamine, quinine on this domino reaction at 55 °C for 6 h. Surprisingly, all these
bases produced inferior results (11ꢀ50% yields of 3aa, entries 13ꢀ18) as compared to
DABCO (92%, 3 h, entry 5).
We propose a possible mechanism for the formation of 3aa as shown in Scheme 3. At
first carbanion ion 1a' is generated from 1a via abstraction of an active methylene proton
by a base which undergoes SN2' reaction with MBH adduct 2a to generate intermediate 4.
The latter further may convert into triene intermediate
5 through elimination of SO3 in
Scheme 3. Probable mechanism of this domino reaction.
the presence of base which is subsequently cyclized to form cyclic intermediate 6 13
.
Finally, the product 3aa forms from intermediate
6 through elimination of HNO2.
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After successfully establishing the reaction parameters for the synthesis of 4,6ꢀdiphenyl
picolinate, the scope and limitation of this reaction were examined by performing the
reaction using a series of 4ꢀarylꢀsubstituted cyclic sulfamidate imines (1a-g) with MBH
acetates derived from nitroolefins (2a-l) under present conditions as shown in Table 2.
Results showed that electron donating (Me, OMe, OBn) substituents on aryl rings of
MBH acetates (2b-2e) are slightly less reactive (3ꢀ5 h vs 2.5ꢀ3 h) towards 1a as compared
to electron withdrawing ones (F, Cl, CN and NO2). However, all the reactions led to high
to excellent yields (84ꢀ93%) of 4,6ꢀdiarylpicolinates (3ab-3ai). Moreover, heteroꢀarylꢀ
substituted MBH acetates (2j and 2k) ran smoothly with 1a by this procedure, delivering
high yields 85% and 86% of desired products 3aj and 3ak respectively. Furthermore,
incorporation of several substituents (Me, MeO, F, Cl and Br) on the aryl rings of cyclic
sulfamidate imines (1b-g) did not show any difficulty towards the annulations with
several MBH acetates (2a-2l) under standard conditions. Consequently, high to excellent
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yields (82ꢀ91%) of corresponding picolinate derivatives (3ba-3gk, ORTEP data of 3bd
(CCDC-1456731, ESI) were isolated with short span of times (3ꢀ6 h). This metalꢀfree
domino procedure is enough mild to sustain several functionalities such as Me, OMe,
OBn, F, Cl, NO2, CN, CO2Et, furan, thiophene etc. Therefore, this method provides
further opportunity for the synthesis of important therapeutic targets through necessary
synthetic modifications of these above functional groups.
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Table 2. Substrate scope of 4,6ꢀdiarylpicolinates synthesis.
R1
O
O
N
OAc
CO2Et
S
O2N
DABCO (1.5 equiv)
THF, 55 °C, 2.5-6 h
1 = 4-MeOC6H4
2c:
R
O
+
R1
2a-k
R
R
N
CO2Et
1a-g
3aa-3gk
1
1
2a
2d
2f
2b
: R = Ph, : R = 4-MeC6H4,
1
2e:
: R = 2,5-(MeO)2C6H3,
R
1 = 3-MeO-4-BnOC6H3
1
1
: R = 4-FC6H4, : R = 4-ClC6H4, : R1 = 4-CNC6H4
2g
2h
: R = 3-O2NC6H4, : R = 2-furyl, : R1 = 2-thiophenyl,
1
1
2i
2j
2k
: R1 = 4-CF3C6H4
2l
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Me
OBn
OMe
F
OMe
OMe
MeO
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
3ab: 3 h, 90%
3ad: 5 h, 86%
3ac: 4 h, 89%
3ae: 5 h,84%
3aa: 3 h, 92%
3af: 2.5 h, 93%
Cl
CN
O2N
O
S
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
3ag:
2.5 h, 91%
3ak: 5 h, 86%
3ah: 2.5 h, 90%
3ba: 3 h, 91%
3ai: 3 h, 87%
3aj: 5 h, 85%
OBn
Me
OMe
Me
Cl
F
OMe
OMe
MeO
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
3bb:
3bd:
3 h, 90%
3bc:
5 h, 85%
4 h, 87%
3bg:
Me
Me
3 h, 88%
3bf: 3 h, 90%
Me
3be: 5 h, 84%
Me
Me
Me
Cl
O
S
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
4 h, 88%
3bj: 5 h, 84%
3bk: 5 h, 83%
Me
Me
3cg: 3 h, 89%
3ea: 4 h, 89%
3da:
3ca:
Cl
3 h, 87%
MeO
MeO
F
CF3
F
OMe
O
MeO
Cl
Cl
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
N
CO2Et
6 h, 82%
N
CO2Et
3gf: 4 h, 88%
Cl
3ga:
3gd:
6 h, 85%
3fl: 4 h, 87%
Cl
4 h, 86%
3fa: 4 h, 90%
Br
Br
Br
3ej:
O
S
N
CO2Et
N
CO2Et
N
3gg:
CO2Et
4 h, 87%
3gj:
3gk: 6 h, 84%
6 h, 82%
Br
Br
Br
Towards the further possible substrate scope, the chemically challenging MBH acetates of
nitrodienes (2m-2n) have been employed as acceptors in the domino reaction with a
variety of 4ꢀarylꢀsubstituted cyclic sulfamidate imines (1a-g) under present conditions.
Interestingly, the cyclic imines (1a, 1b and 1g) attacked nitrodienes (2m and 2n) have
been employed as acceptors in the domino reaction with a variety of 4ꢀarylꢀsubstituted
cyclic sulfamidate imines (1a-g) under present conditions. Interestingly, the cyclic imines
(
1a, 1b and 1g) attacked nitrodienes (2m and 2n) exclusively at the βꢀposition by this
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current procedure. As a consequence, high yields (79ꢀ85%) of corresponding 6ꢀarylꢀ(E)ꢀ
5
6
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8
4ꢀstyrylꢀsubstituted picolinates (3am-3gm) were obtained in Scheme 4. It is noteworthy
to mention that this is the first successful synthetic protocol for the access to ( )ꢀ4ꢀ
E
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styrylpicolinates in a oneꢀpot manner including transition metalꢀsalts mediated reaction.
Scheme 4. Oneꢀpot synthesis of (E)ꢀ6ꢀarylꢀ4ꢀstyrylꢀsubstituted picolinates (3am-3gm).
In order to show the potential utility of the synthesized compounds, picolinate 3aa was
further transformed into a synthetically as well as pharmaceutically useful 2ꢀ
aminopyridine
7 in 78% combined yield (twoꢀstep) via a hydrolysis of ester group of 3aa
by using a LiOH in MeCN/H2O at room temperature, followed by in situ
azidonation/Curtius rearrangement/hydrolysis of resultant picolinic acid using
(PhO)2P(O)N3/Et3N in toluene at heating conditions. Furthermore, 2ꢀaminoꢀ4,6ꢀ
diphenylpyridine (7) was subjected to react with MBH acetate 2g in MeOH, providing a
biologically attractive imidazo[1,2ꢀ
anxiolytic drug Alpidem derivative 915 was synthesized in high yield (82%, twoꢀstep) via
a
]pyridine derivative 814 in 81% yield. Finally,
a hydrolysis of ester group of 9, followed by amidation reaction of the resultant acid with
dipropylamine using EDCI/DMAP as an efficient amide bond coupling reagent in
Ph
Scheme 5.
Ph
(i) LiOH.H2O
MeCN:H2O, 60 °C
12 h
Ph
(i) LiOH.H2O
MeCN:H2O
rt, 5 h
2g
MeOH
rt, 2 h
Ph
Ph
N
N
O
Ph
N
N
Ph
N
CO2Et
Ph
N
NH2
(ii) EDCI, DMAP
Et3N, (nPr)2NH
DMF, rt, 12 h
(ii) (PhO)2P(O)N3
Et3N, toluene
65 to 100 °C, 8 h
EtO2C
9
(nPr)2N
(82% yield, two-step)
3aa
8
7 (78% yield, overall)
Cl
Cl
Scheme 5. Syntheses of 2ꢀaminoꢀ4,6ꢀdiphenylpyridine (7) and Alpidem derivative 9.
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CONCLUSION
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In the current manuscript, we have developed the first, simple, convenient, metalꢀfree
and general new domino synthetic technique for the rapid access to important class of 4,6ꢀ
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diarylpicolinates from several 4ꢀarylꢀ5Hꢀ1,2,3,ꢀoxathiazoleꢀ2,2ꢀdioxides and MBH
acetates of nitroalkenes/nitrodienes in the presence DABCO as a cheap organobase at
heating conditions. Moreover, this metalꢀfree domino technique delivers high to excellent
yields of above title compounds and excels for a wide range of sensitive functional
groups. Furthermore, high yield of anxiolytic drug Alpidem derivative has been
successfully obtained through our synthetic methodology. Therefore, we believe this new
domino method will gain great importance in synthetic organic and medicinal chemistry
as a powerful tactic for the access to functionalized picolinates.
EXPERIMENTAL SECTION
General Information: All the 4ꢀarylꢀ5Hꢀ1,2,3ꢀoxathiazoleꢀ2,2ꢀdoxides (1a-1g)16a and MBH
acetates of nitroolefins/nitrodienes (2a-2l)16b were synthesized by known literature procedures.
All the catalysts were purchased from commercial sources. All the reactions were carried out
either under inert atmosphere or air and monitored by TLC using Merck 60 F254 pre coated silica
gel plates and the products were visualized by UV detection. Flash chromatography was carried
out using silica gel (200ꢀ300 mesh). FTꢀIR spectra were recorded on a KBr plate or neat. 1H and
13C NMR spectra were recorded on a 400 MHz spectrometer. Data for 1H NMR are reported as a
chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
13
multiplet), coupling constant J (Hz), integration, and assignment, data for C are reported as a
chemical shift. High resolutions mass spectral analyses (HRMS) were carried out using ESIꢀ
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TOFꢀMS. Melting points were recorded on an Electro thermal melting points apparatus and are
uncorrected.
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Representative procedure for the synthesis of ethyl 4,6-diphenylpicolinate (3aa):
To a stirred solution of compound 1a (39.4 mg, 0.2 mmol) and 2a (67.39 mg, 0.22 mmol) in THF
(0.5 mL) was added DABCO (33.6 mg, 0.3 mmol) at room temperature. Then the reaction
mixture was heated at 55 °C for 3 h (monitored by TLC). Upon completion of the reaction, the
reaction mixture was extracted with ethyl acetate (3 × 10 mL), washed with water and brine
respectively, and dried over Na2SO4. The combined organic phases were evaporated under
reduced pressure to afford the crude product. Finally the product was obtained in pure form (55.7
mg, 92%) through column chromatography over silicaꢀgel using a mixture of EtOAc/hexane
(1:4, v/v) as the eluent. The product was fully characterized by its spectroscopic data (IR,
1HNMR, 13C NMR and HRMS).
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All the synthesized products (3ab-3gk) in Table 2 and Scheme 4 (3am-3gm) were followed the
above procedure. All the products were characterized by their corresponding spectroscopic data
(IR, 1H , 13C NMR and HRMS).
Ethyl 4,6-diphenylpicolinate (3aa). White solid (55.6 mg, 92%); mp 65‒67 °C; Rf = 0.76
(EtOAc : hexane = 1 : 4); IR (KBr): ν 2984, 2932, 2902, 1714, 1600, 1546, 1425, 1372, 1345 cmꢀ
1; 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.09‒8.13 (m, 3H), 7.73‒7.75 (m, 2H), 7.43‒7.55
(m, 6H), 4.52 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
165.9, 158.6, 150.7, 149.3, 139.0, 138.1, 129.8, 129.6, 129.1, 127.6, 127.4, 121.8, 121.8 (2C),
62.2, 14.6; HRMS (ESI) m/z calcd for C20H17NO2[M+H]+ : 304.1332, found 304.1334.
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Ethyl 6-phenyl-4-(4-methylphenyl)picolinate (3ab). White solid (57.1 mg, 90%); mp 68‒71
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°C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr): ν 2994, 2952, 2925, 2901, 2854, 1715, 1601,
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1544, 1516, 1451, 1430, 1370, 1345, 1279 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H),
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8.11‒8.13 (m, 2H), 8.07 (s, 1H), 7.64‒7.65 (m, 2H), 7.48‒7.52 (m, 2H), 7.42‒7.46 (m, 1H),
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7.32‒7.34 (m, 2H), 4.52 (q, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.49 (t, J = 7.0 Hz, 3H); C NMR
(100 MHz, CDCl3): δ 165.9, 158.5, 150.5, 149.2, 139.9, 139.0, 135.0, 130.2, 129.6, 129.0, 127.6,
127.2, 121.5, 121.4, 62.1, 21.5, 14.6; HRMS (ESI) m/z calcd for C21H19NO2[M+H]+ : 318.1489,
found: 318.1492.
Ethyl 4-(4-methoxyphenyl)-6-phenylpicolinate (3ac). Orange solid (59.3 mg, 89%); mp 79‒
81 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2963, 2926, 2853, 1715, 1606, 1544, 1516,
1
1458, 1433, 1371, 1349, 1255 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 8.06‒8.08 (m,
2H), 8.00 (s, 1H), 7.65‒7.67 (m, 2H), 7.38‒7.48 (m, 3H), 6.98‒7.00 (m, 2H), 4.48 (q, J = 7.0 Hz,
2H), 3.83 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.0, 161.1, 158.5,
150.0, 149.1, 139.1, 130.1, 129.6, 129.0, 128.6, 127.5, 121.1, 121.0, 114.9, 62.1, 55.8, 14.6;
HRMS (ESI) m/z calcd for C21H19NO3[M+H]+ : 334.1438, found 334.1439.
Ethyl 4-(2,5-dimethoxyphenyl)-6-phenylpicolinate (3ad). Yellow solid (62.4 mg, 86%); mp
80‒82 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2961, 2928, 2837, 1719, 1596, 1543,
1
1503, 1466, 1427, 1368, 1303 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 8.07‒8.09 (m,
3H), 7.42‒7.51 (m, 3H), 6.97‒6.98 (m, 3H), 4.50 (q, J = 7.0 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H),
1.47 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.0, 157.9, 154.2, 151.1, 148.5,
148.4, 139.2, 129.5, 129.0, 128.4, 127.7, 124.6, 124.3, 116.5, 115.3, 113.2, 62.1, 56.6, 56.2,
14.6; HRMS (ESI) m/z calcd for C22H21NO4 [M+H]+: 364.1543, found 364.1548.
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Ethyl 4-(4-benzyloxy-3-methoxyphenyl)-6-phenylpicolinate (3ae). Light greenish solid (73.7
mg, 84%); mp 83‒85 °C; Rf = 0.43 (EtOAc : hexane = 1:4); IR (KBr): ν 2982, 2936, 2871, 1715,
1593, 1453, 1516, 1468, 1453, 1430, 1384, 1368, 1348, 1264 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 8.24 (s, 1H), 8.10‒8.12 (m, 2H), 8.03 (s, 1H), 7.47‒7.51 (m, 5H), 7.38‒7.41 (m, 2H), 7.33‒
7.35 (m,1H), 7.26 (s, 2H), 7.01‒7.03 (m, 2H), 5.24 (s, 2H), 4.53 (q, J = 6.8 Hz, 2H), 4.01 (s, 3H),
1.49 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.0, 158.5, 150.5, 150.4, 149.8,
149.2, 139.2, 137.0, 131.1, 129.7, 129.1, 128.9, 128.3, 127.8, 127.5, 121.4, 121.3, 120.1, 114.4,
110.9, 71.3, 62.2, 56.6, 14.8; HRMS (ESI) m/z calcd for C28H25NO4 [M+H]+ : 440.1856, found
440.1857.
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Ethyl 4-(4-fluorophenyl)-6-phenylpicolinate (3af). White solid (59.9 mg, 93% ); mp 90‒92
°C; Rf = 0.80 (EtOAc:hexane = 1:4); IR (KBr): ν 2994, 2952, 2902, 1714, 1605, 1550, 1512,
1
1435, 1371, 1345, 1283, 1238 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 1.5 Hz, 1H),
8.09‒8.12 (m, 2H), 8.02 (d, J = 1.5 Hz, 1H), 7.70‒7.73 (m, 2H), 7.45‒7.52 (m, 3H), 7.19‒7.23
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(m, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ
165.8, 164.0 (JCꢀF = 248.0 Hz), 158.7, 149.6, 149.3, 138.8, 134.1, 134.1, 129.8, 129.3, 129.2,
129.1, 127.6, 121.6, 121.5, 116.7, 116.5, 62.3, 14.6; HRMS (ESI) m/z
C20H16FNO2[M+H]+ : 322.1238, found 322.1241.
calcd for
Ethyl 4-(4-chlorophenyl)-6-phenylpicolinate (3ag). Light greenish solid; (61.4 mg, 91%); mp
91‒93 °C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr): ν 2994, 2950, 2898, 1713, 1602, 1543,
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1491, 1432, 1372, 1345 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.09‒8.11 (m, 2H),
8.02 (s, 1H), 7.66‒7.67 (m, 2H), 7.44‒7.51 (m, 5H), 4.51 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 166.7, 158.7, 149.4 (2C), 138.7, 136.4, 136.0, 129.8, 129.7,
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129.1, 128.7, 127.6, 121.5, 121.4, 62.3, 14.6; HRMS (ESI) m/z calcd for C20H16ClNO2[M+H]+ :
338.0942, found 338.0938.
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Ethyl 4-(4-cyanophenyl)-6-phenylpicolinate (3ah). White solid (59.1 mg, 90%); mp 105‒107
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°C; Rf = 0.46 (EtOAc:hexane = 1:4); IR (KBr): ν 2993, 2951, 2900, 2225, 1716, 1599, 1543,
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1506, 1433 cmꢀ1; H NMR (400 MHz, CDCl3): 8.24 (s, 1H), 8.10‒8.12 (m, 2H), 8.05 (s, 1H),
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7.83 (s, 4H), 7.46‒7.52 (m, 3H), 4.52 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3): δ 165.5, 159.0, 149.6, 148.7, 142.5, 138.4, 133.3, 130.1, 129.2, 128.2, 127.6,
121.6 (2C), 118.5, 113.5, 62.4, 14.6; HRMS (ESI) m/z calcd for C21H16N2O2[M+Na]+ :
351.1104, found 351.1106.
Ethyl 4-(3-nitrophenyl)-6-phenylpicolinate (3ai). White solid (60.6 mg, 87%) ; mp 110‒112
°C; Rf = 0.43 (EtOAc:hexane = 1:4); IR (KBr): ν 2984, 2929, 2871, 1723, 1599, 1531, 1443,
1
1423, 1350 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.34‒8.37 (m, 1H), 8.29 (s, 1H),
8.11‒8.15 (m, 3H), 8.06‒8.08 (m, 1H), 7.72‒7.76 (m, 1H), 7.46‒7.55 (m, 3H), 4.54 (q, J = 7.2
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Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 165.5, 159.2, 149.8, 149.3,
148.2, 139.9, 138.5, 133.4, 130.7, 130.2, 129.3, 127.7, 124.4, 122.5, 121.6 (2C), 62.5, 14.7;
HRMS (ESI) m/z calcd for C20H16N2O4[M+Na]+ : 371.1002, found 371.1027.
Ethyl 4-(2-furyl)-6-phenylpicolinate (3aj). White solid; yield: 85% (49.8 mg); mp 69‒71 °C;
Rf = 0.66 (EtOAc:hexane = 1:4); IR (KBr): ν 2973, 2926, 2905, 2858, 1735, 1612, 1568, 1551,
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1489, 1451, 1428, 1368, 1341, 1247 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.23‒8.24 (m, 1H),
8.09‒8.11 (m, 3H), 7.57‒7.58 (m, 1H), 7.42‒7.51 (m, 3H), 7.00 (d, J = 3.5 Hz, 1H), 6.55‒6.56
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(m, 1H), 4.50 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ
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165.7, 158.6, 151.1, 149.2, 144.4, 139.5, 138.8, 129.7, 129.0, 127.5, 117.9, 117.4, 112.6, 109.8,
62.2, 14.6; HRMS (ESI) m/z calcd for C18H15NO3 [M+H]+ : 294.1125, found 294.1128.
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Ethyl 6-phenyl-4-(2-thiophenyl)picolinate (3ak). Yellow powder (53.2 mg, 86%); mp 75‒77
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°C; Rf = 0.66 (EtOAc:hexane = 1:4); IR (KBr): ν 2975, 2924, 2901, 1737, 1597, 1552, 1477,
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1432, 1367, 1321, 1235, 1212 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.23‒8.24 (m, 1H), 8.08‒
8.10 (m, 2H), 8.02‒8.03 (m, 1H), 7.63‒7.64 (m, 1H), 7.45‒7.52 (m, 4H), 7.16‒7.18 (m, 1H),
4.51 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7, 158.8,
149.4, 143.6, 140.9, 138.7, 129.8, 129.1, 128.8, 128.0, 127.5, 126.3, 119.9, 119.7, 62.3, 14.6;
HRMS (ESI) m/z calcd for C18H15NO2S[M+H]+ : 310.0896, found 310.0904.
Ethyl 4-phenyl-6-(4-methylphenyl)picolinate (3ba). Light yellowish solid (57.7 mg, 91%); mp
63‒65 °C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr): ν 2976, 2923, 2855, 1732, 1600, 1543,
1367, 1238 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.89‒7.92 (m, 3H), 7.58‒7.60 (m,
2H), 7.33‒7.40 (m, 3H), 7.16‒7.18 (m, 2H), 4.39 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 1.35 (t, J =
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7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 165.9, 158.5, 150.5, 149.1, 139.7, 138.0, 136.1,
129.8, 129.6, 129.4, 127.4 (2C),121.4, 121.3, 62.1, 21.6, 14.6; HRMS (ESI) m/z calcd for
C21H19NO2[M+H]+ : 318.1489, found 318.1492.
Ethyl 4,6-di-(4-methylphenyl)picolinate (3bb): Pale yellow solid; yield 90% (59.6 mg); mp
65‒67 °C; Rf = 0.73 (EtOAc:Hexane = 1:4); IR (neat): ν 1713, 1600, 1544, 1514, 1435, 1368,
1344, 1257, 1239 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 1.7 Hz, 1H), 8.03‒8.04 (m,
2H), 8.01 (s, 1H), 7.63‒7.65 (m, 2H), 7.29‒7.33 (m, 4H), 4.52 (q, J = 7.0 Hz, 2H), 2.42 (s, 3H),
2.42 (s, 3H), 1.49 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.0, 158.5, 150.3, 149.0,
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139.8, 139.7, 136.2, 135.1, 130.1, 129.7, 127.4, 127.2, 121.2, 121.1, 62.1, 21.5, 21.5, 14.6;
HRMS (ESI) m/z calcd for C22H21NO2[M+H]+ : 332.1651, found 332.1655.
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Ethyl 4-(4-methoxyphenyl)-6-(4-methylphenyl)picolinate (3bc): Light yellowish solid (60.4
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mg, 87%); mp 78‒80 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2980, 2903, 1716, 1602,
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1543, 1512, 1462, 1434, 1402, 1372, 1348, 1290 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.21 (s,
1H), 8.02 (s, 3H), 7.68‒7.70 (m, 2H), 7.29‒7.30 (m, 2H), 7.02‒7.04 (m, 2H), 4.51 (q, J = 6.8 Hz,
2H), 3.87 (s, 3H), 2.41 (s, 3H), 1.48 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.1,
160.1, 157.5, 148.9, 148.1, 138.7, 135.3, 129.3, 128.8, 127.6, 126.4, 119.9, 119.7, 113.9, 61.1,
54.7, 20.6, 13.6; HRMS (ESI) m/z calcd for C22H21NO3[M+H]+ : 348.1594, found 348.1595.
Ethyl 4-(2,5-dimethoxyphenyl)-6-(4-methylphenyl)picolinate (3bd): Light yellowish solid
(64.1 mg, 85%); mp 80‒82 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2987, 2961, 2940,
2906, 2836, 1717, 1638, 1596, 1541, 1468, 1426, 1302, 1256 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 8.18 (s, 1H), 8.04 (s, 1H), 7.98‒8.00 (m, 2H), 7.28‒7.30 (m, 2H), 6.95‒6.98 (m, 3H), 4.49 (q, J
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= 6.5 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.41 (s, 3H), 1.46 (t, J = 6.5 Hz, 3H); C NMR (100
MHz, CDCl3): δ 166.1, 157.8, 154.2, 151.1, 148.4, 148.2, 139.6, 136.4, 129.7, 128.4, 127.5,
124.2, 124.0, 116.5, 115.2, 113.1, 62.0, 56.6, 56.2, 21.6, 14.6; HRMS (ESI) m/z calcd for
C23H23NO4[M+H]+ : 378.1700, found 378.1697.
Ethyl 4-(4-benzyloxy-3-methoxyphenyl)-6-(4-methylphenyl)picolinate (3be): Light yellowish
solid (76.1 mg, 84%); mp 96‒98 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2855, 1715,
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1593, 1540, 1516, 1463, 1433, 1409, 1380, 1348, 1263 cmꢀ1; H NMR (400 MHz, CDCl3): δ
8.11 (s, 1H), 7.94 (s, 1H), 7.91 (s, 2H), 7.38‒7.39 (m, 2H), 7.29‒7.32 (m, 2H), 7.21‒7.23 (m,
3H), 7.16‒7.17 (m, 2H), 6.91‒6.93 (m, 1H), 5.14 (s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H),
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149.7, 149.0, 139.7, 136.9, 136.2, 131.1, 129.7, 128.9, 128.2, 127.5, 127.4, 121.1, 121.0, 120.1,
114.4, 110.8, 71.2, 62.1, 56.5, 21.6, 14.6; HRMS (ESI) m/z calcd for C29H27NO4[M+H]+ :
454.2013, found 454.2020.
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Ethyl 4-(4-fluorophenyl)-6-(4-methylphenyl)picolinate (3bf). White solid (60.5 mg, 90%); mp
88‒90 °C; Rf = 0.80 (EtOAc:hexane = 1:4); IR (KBr): ν 2989, 2923, 2860, 1712, 1603, 1548,
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1510, 1437, 1372, 1345, 1241 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 7.99‒8.01 (m,
3H), 7.67‒7.70 (m, 2H), 7.27‒7.29 (m, 2H), 7.17‒7.21 (m, 2H), 4.50 (q, J = 7.0 Hz, 2H), 2.40 (s,
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3H), 1.47 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 165.8, 163.9 (JCꢀF = 248.0 Hz)
158.6, 149.4, 149.2, 139.9, 135.9, 134.2, 134.1, 129.8, 129.2 (2C), 127.4, 121.2, 121.0, 116.6,
116.4, 62.2, 21.5, 14.6; HRMS (ESI) m/z calcd for C21H18FNO2[M+H]+ : 336.1394, found
336.1392.
Ethyl 4-(4-chlorophenyl)-6-(4-methylphenyl)picolinate (3bg): Light yellowish solid (61.9 mg,
88%) ; mp 90‒92 °C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr): ν 2976, 2925, 2858, 1724,
1600, 1542, 1491, 1441, 1366, 1242 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 8.01 (s,
1H), 7.99 (s, 2H), 7.64‒7.66 (m, 2H), 7.47‒7.49 (m, 2H), 7.28‒7.30 (m, 2H), 4.51 (q, J = 7.0 Hz,
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2H), 2.41 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 165.8, 158.7, 149.2
(2C), 139.9, 136.5, 135.9, 135.9, 129.8, 129.7, 128.6, 127.4, 121.1, 121.0, 62.2, 21.6, 14.6;
HRMS (ESI) m/z calcd for C21H18ClNO2[M+H]+ : 352.1099, found 352.1100.
Ethyl 4-(2-furyl)-6-(4-methylphenyl)picolinate (3bj): Gummy liquid (51.6 mg, 84%); Rf =
0.66 (EtOAc:hexane = 1:4); IR (KBr): ν 2922, 2853, 1719, 1609, 1548, 1486, 1431, 1371 cmꢀ1;
1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 1.5 Hz, 1H), 8.09 (d, J = 1.3 Hz, 1H), 8.00ꢀ8.02 (m,
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2H), 7.57ꢀ7.58 (m, 1H), 7.28‒7.30 (m, 2H), 7.00‒7.01 (m, 1H), 6.55‒6.57 (m 1H), 4.50 (q, J =
7.2 Hz, 2H), 2.41 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 158.6,
151.3, 149.1, 144.4, 139.9, 139.5, 136.0, 129.8, 127.4, 117.7, 117.1, 112.6, 109.8, 62.2, 21.6,
14.6; HRMS (ESI) m/z calcd for C19H17NO3[M+H]+ : 308.1281, found 308.1286.
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Ethyl 4-(2-thiophenyl)-6-(4-methylphenyl)picolinate (3bk): Yellow powder (53.6 mg, 83%);
mp 80‒82 °C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr): ν 2923, 2855, 1736, 1593, 1548, 1420,
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1366, 1320, 1237 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 1.2 Hz, 1H), 7.98‒8.00 (m,
3H), 7.62 (d, J = 3.8 Hz, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.28‒7.31 (m, 2H), 7.14‒7.16 (m, 1H),
4.51 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
165.8, 158.7, 149.2, 143.5, 141.0, 139.9, 135.9, 129.8, 128.8, 127.8, 127.4, 126.2, 119.6, 119.4,
62.2, 21.6, 14.6; HRMS (ESI) m/z calcd for C19H17NO2S[M+H]+ : 324.1053, found 324.1057.
Ethyl 6-(4-methoxyphenyl)-4-phenylpicolinate (3ca): Yellow powder (53.3 mg, 87%); mp 77‒
79 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2970, 2926, 2852, 1734, 1601, 1543, 1515,
1451, 1415, 1366, 1345, 1234 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 8.06 (d, J = 8.2
Hz, 2H), 7.99 (s, 1H), 7.68‒7.70 (m, 2H), 7.44‒7.50 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H), 4.48 (q, J
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= 7.0 Hz, 2H), 3.83 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 165.9,
161.1, 158.2, 150.5, 149.0, 138.1, 131.5, 129.6, 129.4, 128.9, 127.4, 121.1, 120.9, 114.4, 62.1,
55.6, 14.6; HRMS (ESI) m/z calcd for C21H19NO3[M+H]+ : 334.1438, found 334.1444.
Ethyl 4-(4-chlorophenyl)-6-(4-methoxyphenyl)picolinate (3cg): Yellowish solid (65.5 mg,
89%); mp 92‒94 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2988, 2960, 2936, 2901,
1731, 1601, 1543, 1516, 1487, 1462, 1421, 1366, 1347, 1311 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 8.15 (s, 1H), 8.06‒8.08 (m, 2H), 7.96 (s, 1H), 7.64‒7.66 (m, 2H), 7.47‒7.49 (m, 2H), 7.00‒
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7.02 (m, 2H), 4.50 (q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H); C NMR (100
MHz, CDCl3): δ 165.8, 161.2, 158.3, 149.2 (2C), 136.6, 135.9, 131.3, 129.7, 128.9, 128.7,
120.8, 120.6, 114.5, 62.2, 55.6, 14.6; HRMS (ESI) m/z calcd for C21H18ClNO3[M+Na]+ :
390.0867, found 390.0882.
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Ethyl 6-(4-fluorophenyl)-4-phenylpicolinate (3da): Orange solid; yield 88% (56.5 mg); mp
91‒93 °C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr): ν 2989, 2920, 2856, 1711, 1602, 1547,
1510, 1447, 1419, 1372, 1344, 1259 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 8.10ꢀ8.13
(m, 2H), 8.03 (s, 1H), 7.72‒7.74 (m, 2H), 7.47‒7.55 (m, 3H), 7.16‒7.20 (M, 2H), 4.51 (q, J =
7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 164.2 (JCꢀF = 248.0
Hz) 157.6, 150.9, 149.3, 137.9, 135.2, 129.8, 129.6, 129.5, 127.4, 121.8, 121.4, 116.2, 116.0,
62.3, 14.7; HRMS (ESI) m/z calcd for C20H16FNO2[M+H]+ : 322.1238, found 322.1233.
Ethyl 6-(4-chlorophenyl)-4-phenylpicolinate (3ea): Pale yellow solid; yield: 89% (60.1 mg);
mp 85‒87 °C; Rf = 0.83 (EtOAc:hexane = 1:4); IR (KBr): ν 2983, 2959, 2855, 1725, 1598, 1546,
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1490, 1444, 1406, 1369, 1345, 1242 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 8.06‒
8.08 (m, 3H), 7.71‒7.73 (m, 2H), 7.45‒7.54 (m, 5H), 4.51 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7, 157.3, 150.9, 149.3, 137.8, 137.3, 135.9, 129.8,
129.5, 129.3, 128.8, 127.4, 122.0, 121.4, 62.2, 14.6; HRMS (ESI) m/z
C20H16ClNO2[M+H]+ : 338.0942, found 338.0945.
calcd for
Ethyl 6-(4-chlorophenyl)-4-(2-furyl)picolinate (3ej): Pale yellow solid; Yield: 82% (53.7 mg);
mp 89‒91 °C; Rf = 0.83 (EtOAc:hexane = 1:4); IR (KBr): ν 2980, 2960, 2925, 2853, 1721, 1610,
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1547, 1491, 1368, 1342, 1244 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.03‒8.06 (m,
3H), 7.58‒7.59 (m, 1H), 7.44‒7.46 (m, 2H), 7.01‒7.02 (m, 1H), 6.56‒6.57 (m, 1H), 4.50 (q, J =
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7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 157.3, 151.0, 149.2,
144.6, 139.7, 137.2, 136.0, 129.2, 128.8, 118.2, 117.1, 112.7, 110.1, 62.3, 14.6; HRMS (ESI)
m/z calcd for C18H14ClNO3[M+H]+ : 328.0735, found 328.0751.
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Ethyl 6-(2-chlorophenyl)-4-phenylpicolinate (3fa): White solid; Yield 90% (60.8 mg); mp 90‒
92 °C; Rf = 0.66 (EtOAc:hexane = 1:4); IR (KBr): ν 2991, 2960, 2942, 2901, 1718, 1640, 1601,
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1548, 1499, 1479, 1447, 1425, 1386, 1368, 1343, 1288, 1237 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 8.35 (s, 1H), 8.05 (s, 1H), 7.71‒7.74 (m, 3H), 7.48‒7.54 (s, 4H), 7.34‒7.41 (m, 2H),
4.52 (q, J = 6.5 Hz, 2H), 1.48 (t, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7, 157.9,
149.6, 149.3, 138.9, 137.7, 132.6, 132.3, 130.4, 130.3, 129.8, 129.5, 127.5, 127.5, 126.2, 122.1,
62.3, 14.7; HRMS (ESI) m/z calcd for C20H16ClNO2[M+H]+ : 338.0942, found 338.0943.
Ethyl 6-(2-chlorophenyl)-4-(4-trifluoromethylphenyl)picolinate (3fl): Pale yellow Solid;
Yield: 87% (70.6 mg); mp 99‒101 °C; Rf = 0.56 (EtOAc:hexane = 1:4); IR (KBr): ν 2989, 2924,
2854, 1715, 1605, 1546, 1378, 1327, 1256 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 1.4
Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 7.77‒7.85 (m, 4H), 7.71‒7.74 (m, 1H), 7.48ꢀ7.50 (m, 1H),
7.35‒7.42 (m, 2H), 4.52 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 165.4, 158.1, 149.5, 148.2, 141.2, 141.2, 138.5, 132.5, 132.3,131.6, 130.5, 130.4,
128.0, 127.6, 126.6, 126.5, 126.5, 126.5, 126.5, 125.5, 122.8, 122.1, 62.5, 14.6; HRMS (ESI)
m/z calcd for C21H15ClF3NO2[M+H]+ : 406.0816, found 406.0819.
Ethyl 6-(4-bromophenyl)-4-phenylpicolinate (3ga): Light green solid; yield 86 % (65.7 mg);
mp 93ꢀ95 °C; Rf = 0.83 (EtOAc:hexane = 1:4); IR (KBr):ν 2982, 2926, 2901, 2854, 1727, 1596,
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1548, 1488, 1442, 1405, 1369, 1345 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.04 (s,
1H), 7.99‒8.01 (m, 2H), 7.72‒7.73 (m, 2H), 7.61‒7.63 (m, 2H), 7.47‒7.55 (m, 3H), 4.51 (q, J =
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137.8, 137.8, 132.2, 129.9, 129.5, 129.1, 127.4, 124.3, 122.1, 121.4, 62.3, 14.6; HRMS (ESI)
m/z calcd for C20H1679BrNO2[M+H]+ : 382.0437, found 382.0457; HRMS (ESI) m/z calcd for
C20H1681BrNO2[M+H]+ : 384.0418, found 384.0434.
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Ethyl 6-(4-bromophenyl)-4-(2,5-dimethoxyphenyl)picolinate (3gd): Orange solid; yield: 85%
(75.2 mg) ; mp 99‒101 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2960, 2933, 2834, 1734,
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1639, 1598, 1545, 1495, 1462, 1421, 1400, 1371, 1339, 1301, 1278, 1249 cmꢀ1; H NMR (400
MHz, CDCl3): δ 8.21 (s, 1H), 8.03 (s, 1H), 7.96‒7.98 (m, 2H), 7.59‒7.62 (m, 2H), 6.96‒6.97 (m,
3H), 4.49 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 165.8, 156.6, 154.2, 151.0, 148.6, 148.6, 138.0, 132.2, 129.2, 128.1, 124.6,
124.3, 124.1, 116.5, 115.4, 113.1, 62.1, 56.6, 56.2, 14.6; HRMS (ESI) m/z calcd for
C22H2079BrNO4[M+H]+ : 442.0648, found 442.0656; HRMS (ESI) m/z
C22H2081BrNO4[M+H]+ : 444.0629, found 444.0644.
calcd for
Ethyl 6-(4-bromophenyl)-4-(4-fluorophenyl)picolinate (3gf): Pale yellow solid; Yield: 88%
(70.4 mg); mp 100‒102 °C; Rf = 0.83 (EtOAc:hexane = 1:4); IR (KBr): ν 2987, 2925, 2905,
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1717, 1640, 1603, 1549, 1512, 1490, 1439, 1397, 1369, 1345, 1281 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 8.22 (s, 1H), 7.98‒8.00 (m 3H), 7.69‒7.72 (m, 2H), 7.60‒7.62 (m, 2H), 7.19‒7.23 (m,
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2H), 4.51 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 165.6,
164.0 (JCꢀF = 248.0 Hz), 157.4, 149.8, 149.4, 137.7, 133.9, 132.3, 129.3, 129.1, 124.4, 121.8,
121.1, 116.7, 116.5, 62.3, 14.6; HRMS (ESI) m/z calcd for C20H1579BrFNO2[M+H]+ : 400.0343,
found 400.0352; HRMS (ESI) m/z calcd for C20H1581BrFNO2[M+H]+ : 402.0323, found
402.0337.
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Ethyl 6-(4-bromophenyl)-4-(4-chlorophenyl)picolinate (3gg): Pale yellow solid; Yield: 87%
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1H), 7.98‒8.00 (m, 2H), 7.97 (s, 1H), 7.61‒7.67 (m, 4H), 7.49‒7.51 (m, 2H), 4.51 (q, J = 7.0 Hz,
2H), 1.47 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.6, 157.5, 149.6, 149.5, 137.6,
136.2, 136.2, 132.3, 129.8, 129.1, 128.7, 124.5, 121.8, 121.1, 62.4, 14.6; HRMS (ESI) m/z calcd
for C20H1579BrClNO2[M+H]+ : 416.0047, found 416.0058; HRMS (ESI) m/z calcd for
C20H1581BrClNO2[M+H]+ : 418.0027, found 418.0037.
Ethyl 6-(4-bromophenyl)-4-(2-furyl)picolinate (3gi): Brown solid; Yield: 82% (61.0 mg);
mp100‒102 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr): ν 2974, 2925, 2855, 1730, 1609,
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1546, 1487, 1418, 1367, 1338, 1241 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 8.05 (s,
1H), 7.96‒7.98 (m, 2H), 7.59‒7.61 (m, 3 H), 7.00‒7.01 (m, 1H), 6.56 (s, 1H), 4.50 (q, J = 7.2
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Hz, 2H), 1.47 (t, J = 7.04 Hz, 3H); C NMR (100 MHz, CDCl3): δ 164.5, 156.3, 149.9, 148.2,
143.5, 138.7, 136.6, 131.1, 128.0, 123.3, 117.1, 116.0, 111.6, 109.1, 61.2, 13.6; HRMS (ESI)
m/z calcd for C18H1479BrNO3[M+H]+ : 372.0230, found 372.0245; HRMS (ESI) m/z calcd for
C18H1481BrNO3[M+H]+ : 374.0210, found 374.0225.
Ethyl 6-(4-bromophenyl)-4-(2-thiophenyl)picolinate (3gk): Yellowish solid ; yield: 84% (65.2
mg); mp 101‒103 °C; Rf = 0.73 (EtOAc:hexane = 1:4); IR (KBr): ν 2979, 2925, 2901, 2856,
1731, 1598, 1549, 1485, 1443, 1422, 1368, 1323, 1239, 1211 cmꢀ1.1H NMR (400 MHz, CDCl3):
δ 8.23‒8.24 (m, 1H), 7.98‒7.99 (m, 2H), 7.96 (s, 1H), 7.63‒7.64 (m, 2H), 7.61 (s, 1H), 7.47‒
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7.48 (m, 1H), 7.16‒7.19 (m, 1H), 4.51 (q, J = 7.0 Hz, 1H), 1.48 (t, J = 7.0 Hz, 3H); C NMR
(100 MHz, CDCl3): δ 165.6, 157.3, 151.0, 149.3, 144.6, 139.7, 137.6, 132.2, 129.0, 124.3, 118.2,
117.0, 112.7, 110.1, 62.3, 14.6; HRMS (ESI) m/z calcd for C18H1479BrNO2S[M+H]+ : 388.0001,
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389.9988.
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(E)-Ethyl 6-phenyl-4-styrylpicolinate (3am): Light yellow liquid; Yield: 85% (56.0 mg); Rf =
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0.80 (EtOAc:hexane = 1:4); IR (KBr): ν 3059, 2980, 1738, 1714, 1635, 1595, 1546, 1432, 1370,
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1252, 1193, 1084, 1025 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 8.09 (d, J = 7.6 Hz,
2H), 7.91 (s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.39‒7.52 (m, 7H), 7.12‒7.18 (m, 1H), 4.52 (q, J =
7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7, 158.3, 148.8, 146.6,
138.7, 135.9, 134.1, 129.4, 129.0, 128.9, 128.8, 127.3, 127.1, 125.5, 120.9, 120.3, 61.9, 14.3;
HRMS (ESI) m/z calcd for C22H19NO2[M+H]+ : 330.1489, found 330.1478.
(E)-Ethyl 4-(4-methoxystyryl)-6-phenylpicolinate (3an): Light yellow gummy liquid; Yield:
82% (58.9 mg); Rf = 0.65 (EtOAc:hexane = 1:4); IR (neat): ν 1738, 1714, 1591, 1579, 1545,
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1510, 1435, 1249 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 8.01 (d, J = 7.6 Hz, 2H),
7.81 (s, 1H), 7.31‒7.46 (m, 6H), 6.85‒6.95 (m, 2H), 4.43 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 1.41
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.1, 160.7, 158.5, 149.0, 147.3, 139.1,
134.0, 129.6, 129.0, 129.0, 128.9, 127.5, 123.5, 120.9, 120.4, 114.7, 62.2, 55.7, 14.7; HRMS
(ESI) m/z calcd for C23H21NO3 [M+H]+ : 360.1594, found 360.1595.
(E)-Ethyl 4-styryl-6-(4-methylphenyl)picolinate (3bm): Light yellow liquid; Yield: 80% (54.9
mg); Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr): ν 3029, 2979, 2855, 1738, 1714, 1636,1596,
1
1546,1447, 1424, 1253 cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.92 (d, J = 7.8 Hz,
2H), 7.81 (s, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.17‒7.38 (m, 6H), 7.03‒7.07 (m, 1H), 4.43 (q, J =
7.0 Hz, 2H), 2.34 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 158.3,
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148.8, 146.5, 139.5, 136.0, 135.9, 134.0, 129.5, 129.0, 128.9, 127.2, 127.1, 125.6, 120.6, 120.0,
61.9, 21.3, 14.4; HRMS (ESI) m/z calcd for C23H21NO2[M+H]+ : 344.1645, found 344.1635.
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(E)-Ethyl 6-(4-bromophenyl)-4-styrylpicolinate (3gm). Light yellow gummy liquid; Yield:
79% (67.7 mg); Rf = 0.73 (EtOAc:hexane = 1:4); IR (KBr): ν 3058, 2979, 2923, 1737, 1716,
1635, 1597, 1545, 1491, 1446, 1251 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.98 (d, J
= 8.0 Hz, 2H), 7.88 (s, 1H), 7.57‒7.63 (m, 4H), 7.35‒7.47 (m, 4H), 7.11‒7.16 (m, 1H), 4.51 (q, J
= 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.5, 157.0, 148.9,
146.8, 137.5, 135.8, 134.4, 131.9, 129.1, 128.9, 128.8, 127.2, 125.2, 124.0, 120.5, 62.0, 14.3;
HRMS (ESI) m/z calcd for C22H1879BrNO2[M+H]+ : 408.0594, found 408.0614; HRMS (ESI)
m/z calcd for C22H1881BrNO2[M+H]+ : 410.0574, found 410.0607.
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Synthesis of 2-amino-4,6-diphenylpyridine (9). LiOH.H2O (210 mg, 5.0 mmol) was added to a
stirred solution of ethyl 4,6ꢀdiphenylpicolinate (3aa, 303.3 mg, 1.0 mmol) in in MeCN/H2O
(5.0 mL, 4:1) at room temperature. Then the reaction mixture was allowed to stir for 5 h
(monitored by TLC). After completion of the reaction, organic solvent was removed by rotary
evaporator and acidified by 1M acetic acid. Then water layer was extracted with ethyl acetate (5
× 10 mL), washed with brine solution and dried over Na2SO4. Evaporation of the solvent left the
crude 4,6ꢀdiphenylpicolinic acid which was reasonable pure and directly used for the next step
without further purification.
A mixture of resultant 4,6ꢀdiphenylpicolinic acid,
DPPA (385.0 mg, 1.4 mmol), and
triethylamine (405.0 mg, 4.0 mmol) in toluene (2.0 mL) was heated at 65 °C for 2 h and then 100
°C for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was
extracted with ethyl acetate (3 × 10 mL) before being quenched with water. The combined
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organic layer was washed with brine solution and dried over Na2SO4. Afterwards, the organic
phase was concentrated under reduced pressure to furnish the crude product. It was purified by
flash chromatography over silica gel using EtOAc/hexane (2:3 v/v) as the eluent to give 2-
aminoꢀ4,6ꢀdiphenylpyridine (7) in 78% yield (191.9 mg, overall ).
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2-Amino-4,6-diphenylpyridine (7).17 Pale yellow solid; Rf = 0.50 (EtOAc:hexane = 2:3); 1H
NMR (400 MHz, CDCl3): δ 7.97 (d, J = 7.6Hz, 2H), 7.64 (d, J = 7.4Hz, 2H), 7.39ꢀ7.49 (m, 6H),
13
7.31 (s, 1H), 6.67 (s, 1H), 4.66 (br s, 2H); C NMR (100 MHz, CDCl3): δ 158.8, 156.5, 151.2,
139.5, 139.0, 128.8, 128.7, 128.7, 128.5, 126.9 (2C), 110.0, 105.1; HRMS (ESI) m/z calcd for
C17H14N2[M+H]+: 247.1230, found 247.1228.
Typical procedure for the synthesis of ethyl 2-(2-(4-chlorophenyl)-5,7-diphenylimidazo[1,2-
a]pyridin-3-yl)acetate (8).11b 2ꢀAminoꢀ4,6ꢀdiphenylpyridine (7, 123.0 mg, 0.5 mmol) and MBH
acetate (2g, 180.23 mg, 0.55 mmol) were stirred in MeOH (4.0 ml) for 2 h (monitored by TLC).
Upon completion of the reaction, the reaction mixture was extracted by ethyl acatate (3 × 10 mL)
before being removed MeOH. The combined organic layer was washed with brine solution, dried
over sodium sulphate. The organic phase was removed by rotary evaporator to furnish the crude
product which was purified by flash chromatography over silica gel (EtOAc/hexane = 2:3 as an
eluent) to give ethyl 2ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ5,7ꢀdiphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetate (8,
81% yield) as yellow solid product.
Ethyl 2-(2-(4-chlorophenyl)-5,7-diphenylimidazo[1,2-a]pyridin-3-yl)acetate (8). Yellow
solid; Rf = 0.45 (EtOAc:hexane = 2:3); yield 81% (189.0 mg); IR (neat): ν 1731, 1597, 1545,
1487, 1473, 1367, 1254, 1186 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.69 (d, J = 7.6
Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.39ꢀ7.54 (m, 10H), 6.96 (s, 1H), 3.89 (q, 7.2 Hz, 2H), 3.54 (s,
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2H), 1.10 (t, J = 7.2Hz, 3H); C NMR (100 MHz, CDCl3): δ 169.7, 146.9, 146.2, 138.6, 138.3,
137.1, 134.4, 134.0, 132.9, 130.1, 129.9, 129.5, 129.0, 128.7, 128.3, 128.2, 126.7, 115.2, 114.8,
113.5, 61.0, 32.3, 13.9; HRMS (ESI) m/z calcd for C29H23ClN2O2 [M+H]+: 467.1521, found
467.1509.
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Experimental
procedure
for
the
synthesis
of
2-(2-(4-Chlorophenyl)-5,7-
diphenylimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (9).
LiOH.H2O (126.0 mg, 3.0 mmol) was added at room temperature to a stirred solution of ethyl
2ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ5,7ꢀdiphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetate (8, 140.0 mg, 0.3 mmol)
in MeCN/H2O (4.0 mL, 3:1). Afterwards, the reaction mixture was heated at 60 °C for 12 h.
After completion of the reaction (monitored by TLC), solvent was removed by rotary evaporator
to provide the crude mass which was acidified with 1M acetic acid solution. Then water layer
was extracted with ethyl acetate (5 × 10 mL). The combined organic layer was washed with
brine, dried over Na2SO4. Next the organic phase was evaporated under reduced pressure to
obtain the crude imidazopyridine carboxylic acid as white solid which was sufficiently pure to
carry out next step.
A mixture of imidazopyridine carboxylic acid, EDCI.HCl (0.45 mmol), Et3N (1.0 mmol),
DMAP (0.06 mmol) and N,Nꢀdipropyl amine (0.6 mmol) in DMF (1.0 mL) was stirred at room
temperature under argon atmosphere for 12 h (monitored by TLC). After that, the reaction
mixture was extracted with ethyl acetate (3 × 10 mL) before being quenched with saturated
NH4Cl solution. Combined rganic layers were washed with brine and dried over Na2SO4. Next,
evaporation of organic slovent left the crude material which was purified by column
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chromatography over silicaꢀgel (EtOAc/hexane 1:4 as a mixture of solvent) to furnish the pure
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product (9, 128.4 mg, 82% yield, twoꢀstep).
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2-(2-(4-Chlorophenyl)-5,7-diphenylimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (9).
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Yellow solid; yield 82%; Rf = 0.40 (EtOAc:hexane = 2:3); H NMR (400 MHz, CDCl3): δ 7.89
(s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.36‒7.58 (m, 12H), 6.89 (s, 1H), 3.49 (s, 2H), 3.09 (t, J = 7.2
Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H), 1.45ꢀ1.51 (m, 2H), 1.19ꢀ1.24 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H),
0.73 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.2, 146.9, 145.6, 138.5, 138.4,
136.7, 135.2, 133.6, 133.4, 130.1, 130.0, 129.1, 129.0, 128.5, 128.1, 128.0, 126.7, 116.6, 115.1,
113.6, 49.6, 48.4, 31.5, 21.8, 20.9, 11.5, 11.2; HRMS (ESI) m/z calcd for C33H32ClN3O [M+H]+:
522.2307, found 522.2313.
ACKNOWLEDGEMENTS
The authors thank DST (Project No. SB/S1/OCꢀ19/2013) research grants, Govt. of India
for the generous financial support and SIC facility, IIT Indore. The authors wish to thank
CSIR for the fellowship of D. Majee.
ASSOCIATED CONTENT
Supporting information
“This material is available free of charge via the Internet at http://pubs.acs.org.” Copies of
1
13
IR, H and NMR spectra for the products, Xꢀray crystal data for compound 3bd (CIF
)
are available in ESI.
NOTES
The authors declare no competing financial interest
REFERENCES
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(1) (a) Fraser, H. L.; Hopper, D. W.; Kutterer, K. M. K.; Crombie, A. L. In Progress In
Heterocyclic Chemistry; Gribble, G. W.; Joule, J. A., Eds.; Elsevier: Amsterdam, 2008; vol.
19, pp 314‒352. (b) Hopper, D. W.; Kuterer, K. M. K.; Crombie, A. L.; Clemens, J. J.; In
Progress In Heterocyclic Chemistry; Gribble, G. W.; Joule, J. A., Eds.; Elsevier, Amsterdam,
2009; Vol. 20, pp 289‒332. (c) Hill, M. D. Chem. Eur. J. 2010, 16, 12052. (d) Fu, P.;
Wang, S. X.; Hong, K.; Liu, P. P.; Wang, Y.; Zhu, W. M. J. Nat. Prod. 2011, 74, 1751. (e)
Donohoe, T. J.; Jones, C. R.; Kornahrens, A. F.; Barbosa, L. C. A.; Walport, L. J.; Tatton,
M. R.; O’Hagan, M.; Rathi, A. H.; Baker, D. B. J. Org. Chem. 2013, 78, 12338.
(2) a) Roth, H. J.; Kleemann, A. Drug Synthesis in Pharmaceutical Chemistry; John Wiley and
Sons: New York, 1988; Vol. 1. (b) Chen, Y. L.; Braselton, J.; Forman, J.; Gallaschun, R. J.;
Mansbach, R.; Schmidt, A. W.; Seeger, T. F.; Sprouse, J. S.; Tingley, III, F. D.; Winston,
E.; Schulz, D. W. J. Med. Chem. 2008, 51, 1377.
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
25
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27
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43
44
45
46
47
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52
53
54
55
56
57
58
59
60
(3) (a) Functional Organic Materials, ed. Müller, T. J. J.; Bunz, U. H. F. WileyꢀVCH,
Weinheim, 2007; (b) Sasabe, H.; Kido, J. Chem. Mater. 2011, 23, 621.
(4) (a) Masters, R. A.; Lo, W. C.; Gast, R. E. Aminopyralid. In Modern Crop Protection
Compounds, 2nd ed.; Kraemer, W., Ed.; WileyꢀVCH: Weinheim, 2012; p 287. (b) G. D.
Henry, Tetrahedron 2004, 60, 6043.
(5) Kang, N.ꢀG.; Changez, M.; Lee, J.ꢀS. Macromolecules 2007, 40, 8553.
(6) (a) Bora, D.; Deb, B.; Fuller, A. L.; Slawin, A. M. Z.; Derek Woollins, J.; Dutta, D. K.
Inorg. Chim. Acta 2010, 363, 1539. (b) Chan, Y.ꢀT.; Moorefield, C. N.; Soler, M.; Newkome,
G. R. Chem. Eur. J. 2010, 16, 1768.
(7) (a) Murugan, R.; Scriven, E. F. V. Aldrichimica Acta 2003, 36, 21. (b) De Rycke, N.;
Couty, F.; David, O. R. P. Chem. Eur. J. 2011, 17, 12852.
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5
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7
8
9
(8) (a) Eliel, E. L.; Marbride, R. T. Kaufmann, S. J. Am. Chem. Soc. 1953, 75, 4291. (b) Allais,
C.; Grassot, J.ꢀM.; Rodriguez, J.; Constantieux, T. Chem. Rev. 2014, 114, 10829. (c) Simon,
C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (d) Neely, J. M.; Rovis,
T. Org. Chem. Front. 2014, 1, 1010. (e) Wang, Y.ꢀF.; Toh, K. K.; Ng, E. P. J.; Chiba, S. J.
Am. Chem. Soc. 2011, 133, 6411. (f) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.ꢀH. Org.
Lett. 2008, 10, 325. (g) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2012,
77, 2501. (h) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756. (i) Jiang, Y.; Park,
C.ꢀM. Chem. Sci. 2014, 5, 2347.
10
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59
60
(9) (a) Johnson, P.L.; Renga, J. M.; Galliford, C. V.; Whiteker, G. T.; Giampietro, N. C. Org.
Lett. 2015, 17, 2905. (b) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66; (c) Zhu,
C.; Bi, B.; Ding, Y.; Zhang, T.; Chen, Q.ꢀY. Org. Biomol. Chem. 2015, 13, 6278. (d) Yu, J.;
Kim, K. H.; Lee, H. J.; Kim, J. N. Bull. Korean Chem. Soc. 2013, 34, 3027. (e) Zhu, X.;
Wang, Y.ꢀF.; Zhang, F.ꢀL.; Chiba, S. Chem. Asian J. 2014, 9, 2458. (f) Lu, J.ꢀY.; Arndt, H.ꢀ
D. J. Org. Chem. 2007, 72, 4205.
(10) (a) Majee, D.; Srivastava, A.; Mobin, S. M.; Samanta, S. RSC Adv. 2013, 3, 11502. (b)
Majee, D.; S. Biswas, S. M. Mobin and S. Samanta, Tetrahedron Lett. 2014, 55, 4553.
(11) (a) Nair, D. K.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett. 2012, 14, 4580. (b)
Gopi, E.;
Kumar, T.; MennaꢀBarreto, R. F. S.; Valença, W. O.;
Júnior, E. N. da
Silva; Namboothiri, I. N. N. Org. Biomol. Chem. 2015, 13, 9862. (c) Huang, W.ꢀY.; Chen,
Y.ꢀC.; Chen, K.; Chem. Asian. J. 2012, 7, 688. (d) Magar, D. R.; Ke, Y.ꢀJ.; Chen, K. Asian J.
Org. Chem. 2013, 2, 330.
(12) (a) Dagar, A.; Biswas, S.; Samanta, S. RSC Adv. 2015, 5, 52497. (b) Biswas, S.; Jaiswal,
P. K.; Singh, S.; Mobin, S. M.; Samanta, S. Org. Biomol. Chem. 2013, 11, 7084. (c) Jaiswal,
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