Metal- and Solvent-Free Approach to Diversely Substituted Picolinates via Domino Reaction of Cyclic Sulfamidate Imines with β,γ-Unsaturated α-Ketocarbonyls

Article abstract of DOI:10.1021/acs.joc.7b01792

An efficient, solvent-free, and eco-friendly domino reaction of 5/6-membered cyclic sulfamidate imines with a variety of β, γ-unsaturated α-ketocarbonyls in neat conditions under MW irradiation promoted by DABCO as a solid organobase has been developed for the rapid construction of a novel class of densely functionalized picolinates. This interesting metal-solvent-free tactic allows a wide range of useful functionalities on the aryl rings and delivers good to excellent yields of the aforesaid aza-heterocycles within short time spans (20-40 min). A biologically promising imidazo[1,2-a]pyridine was successfully synthesized through our unique procedure.

Full text of DOI:10.1021/acs.joc.7b01792

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Article
A Metal-and Solvent-Free Approach to Diversely
Substituted Picolinates via Domino Reaction of Cyclic
Sulfamidate Imines with #,#-Unsaturated #-Ketocarbonyls
Soumen Biswas, Debashis Majee, Soumitra Guin, and Sampak Samanta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01792 • Publication Date (Web): 21 Sep 2017
Downloaded from http://pubs.acs.org on September 22, 2017
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A Metal-and Solvent-Free Approach to Diversely Substituted Picolinates via
Domino Reaction of Cyclic Sulfamidate Imines with β,γ-Unsaturated α-
Ketocarbonyls
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Soumen Biswas, Debashis Majee, Soumitra Guin and Sampak Samanta*
Discipline of Chemistry, Indian Institute of Technology Indore, Simrol, Indore, 453552, Madhya
Pradesh, India.
*Corresponding author. Tel +91-731-2438753
Email: sampaks@iiti.ac.in
O
R2
N
O
N
O
.
S
e
q
R1
DAB
CO
t
1
0
(
)
R3
O
-
,
,
nea
m n
i
MW 2 4
0 0
+
R3
-
O
R1
v n r
so e
R
ee
R2
ar
R
l
t f
f
-
R
O
,
,
me a ree
=
R2
t l
a
O
e eroar
yl h t
yl
-
x m
e a
es
O
O
N
60
p
l
x
o
n r
ee
,
,
a
e
id t f
roa su s ra e sco e
S
s r
R3
a
n
ty yl lky yl lkyl
-
O
43 93
%
,
,
n
=
b
d
b t t
p
x
e o
th y ph yl
-
as reac on
m n
i
t
ti
f
0 0
2 4
(
)
R1
y y
l
s r
t
x
n
≤
e s
93
e ce e
ll t yi ld
eco
r en
f i dly
%
(
)
,
-
=
R1 H M
e
ABSTRACT: An efficient, solvent-free and eco-friendly domino reaction of 5/6-membered
cyclic sulfamidate imines with a variety of β,γ-unsaturated α-ketocarbonyls in a neat condition
under MW irradiation promoted by DABCO as a solid organobase has been developed for the
rapid construction of a novel class of densely functionalized picolinates. This interesting metal-
solvent-free tactic allows allows a wide range of useful functionalities on the aryl rings and
delivers good to excellent yields of the aforesaid aza-heterocycles within short span of times (20-
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40 min). A biologically promising imidazo[1,2-a]pyridine was successfully synthesized through
5
6
our unique procedure.
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KEYWORDS: Cyclic sulfamidate imine, β,γ-unsaturated α-ketocarbonyl, functionalized
pyridines, microwave-assisted synthesis, neat condition, metal-free, green method.
The pyridine rings represent one of the most fascinating classes of aza-heterocyclic
molecules which are commonly encountered in numerous biologically active natural
products1, top-selling marketable drugs2, active pharmaceuticals,3 advanced functional
materials,4 agrochemicals,5 metal complexes6 and catalysts7. Furthermore, this most
studied aza-heterocyclic ring is also an essential subunit of vitamins8 (B6 and B3) and
enzymes9 in our body which regulates many therapeutic responses. Therefore, the design
and development of a new, efficient, green and metal-free based new protocol for the
synthesis of interesting functionalized pyridines remains a pivotal research area in
synthetic and medicinal chemistry. In this context, several traditional and modern
protocols have been documented for the access to functionalized pyridine scaffolds since
the inception of pyridine synthesis which include condensation reaction involving
ammonia/amines and 1,5-dicarbonyls/alkylaldehydes (Chichibabin method),10 tandem
reaction of enamines (in situ generated enamines) with enones/ynones (Tsuda/Bohlmann–
Rahtz methods),11 pseudo four-component reaction between aldehydes and β-keto esters
in the presence ammonia (Hantzsch pyridine synthesis)12, multicomponent reaction,13 6π-
aza-electrocylization14 etc. Lately, transition-metal catalyzed [4+2]15/[2+2+2]16
cycloaddition reactions of α,β-unsaturated oximes/nitriles/enamides with alkynes have
emerged as powerful methods for the construction of unsymmetrical pyridine scaffolds.
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Very recently, an alternative, atom-economical route to direct functionalization on
pyridine ring has also been developed through a C-H bond activation catalyzed by several
transition-metal-salts17. In spite of remarkable development in the synthesis of pyridines,
the efficient metal-free access to versatile substituted picolinates has been
underdeveloped18 even though they have proven biological and pharmaceutical
significance.1a-c Towards the synthesis of picolinates, Zhu’s research group has nicely
documented a three-component approach to picolinate derivatives from β,γ-unsaturated α-
ketoesters, enolizable ketones and ammonium acetate promoted by CAN/pyrrolidine
(Scheme 1a)18a. Moreover, Rovis and his coworkers have discovered an elegant method
for the regioselective synthesis of picolinates through a [4+2] cycloaddition reaction of
α,β-unsaturated oxime esters with acrylates at 85 °C in the presence of Rh-salt/AgOAc as
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combined catalytic system (Scheme 1b)18b. Furthermore,
Rh-(III)-catalyzed
oxadiazolone-directed alkenyl C-H coupling with β-alkynyl esters was reported by Zhu
et al. (Scheme 1c).18d Nevertheless, the above procedures are associated with certain
drawbacks like poor yields due to multiple side products, drastic reaction conditions, use
of expensive and precious metal-salts, limited substrate scope etc. On the other hand, our
group also disclosed a DABCO-promoted one-pot synthesis of 2,6-diarylpicolinates in
THF involving cyclic sulfamidate imines as important synthetic precursors.19 However,
this method shows varying degrees of achievements as well as limitations such as
prolonged reaction times, use of a toxic and hazardous organic solvent (THF) as well as
excess amount of a base, applicable for only aryl-substituents. Thus, an alternative,
general, solvent-free and environmentally sustainable procedure is urgently required for
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the quick synthesis of picolinate derivatives with multiple substitutions including alkyl
group on the pyridine rings.
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As part of our ongoing research in the development of metal-free based new synthetic
techniques for the construction of pyridine derivatives,20 here in, we further report a
unique, green method for the straightforward access to diversely functionalized pyridine
derivatives through a domino Michael-elimination-cyclization reaction between several
5/6-membered cyclic sulfamidate imines and a variety of γ-substituted-β,γ-unsaturated α-
ketocarbonyls in a neat condition irradiated by microwave using 1.0 equiv. of DABCO as
an organic base (Scheme 1d).
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u s wor :
k
Zh
R
O
R1
R2
c
A
NH
4O
R2
a
1
e
+
M
R1
CO2
e
NH
4 2C
N
O3
t M
(
)
(
)
e
M
CO2
N
, ,
O
rro ne r
e
H
O
R
R
py lidi
'
v
o s
w r
o
i
k
R1
R
Rh p∗
l
]
A
A
,
R
R
c
v
Pi
C C 2 2 gO
Et
R
CO2
O
[
N
1b
+
°
,
c
D E A
C /
H
O
8
5
C
N
R1
Et
CO2
R1
'
u s wor :
Zh k
Et
CO2
R2
Rh p∗
C C 2 2
l
K A
O
,
O
c
[
]
c
1
O
+
-
°
,
,
N
H
x n
o a e
1 4 di
80
C
H2N
N
Et
CO2
R2
R1
w r :
s
Thi
o
k
-
-
-
me a so ven ox an ree
t l
l
t
id t f
!
R2
N
O
,
O
O
N
nea
t
i
DAB
CO
R1
R3
-
S
,
m n
MW 2 4
0 0
O
+
1d
R3
O
R2
R
R1
R
O
Scheme 1: Different protocols for the synthesis of picolinates
By taking 4-phenyl-5H-1,2,3-oxathiazole-2,2-dioxide (1a) as a suitable nucleophile21 and
(E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a) as model reactants, the initial reaction was
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performed in THF at room temperature in the presence of DABCO (0.5 equiv, entry 1,
Table 1). Interestingly, after 24h, 32% yield of expected 4,6-diphenylpicolinate (3aa) was
isolated in a pure form. This fascinating result motivated us to examine this domino
reaction in detail. Upon increasing the reaction temperature to 70 °C, after 5h, the
compound 3aa was afforded 59% yield (entry 2). Furthermore, by using 1.0 equiv of
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Table 1. Optimization Reaction Conditions.a
Ph
Ph
O
O
O
O
O
O
S
S
con ons
Et
CO
ti
di
N
N
CO22Et
O
O
+
conditions
+
Ph
Ph
N
N
3aa
Et
CO
CO22Et
Ph
Ph
Ph
Ph
a
a
aa
1
2
3
1a
2a
entry
base
solvent
temp (ᵒC)
rt
time
yield (%)b
1c
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
THF
THF
THF
THF
neat
neat
neat
neat
neat
neat
24h
5h
36
59
81
83
85
91
32
28
55
36
2c
3d
4e
5
70
70
5h
70
5h
70
2h
6
MW
MW
MW
MW
MW
20 min
20 min
20 min
20 min
20 min
7
8
DIPEA
DMAP
Et3N
9
10
aUnless otherwise noted, all of the reactions were performed with 1a (0.2 mmol), 2a (0.22
mmol), and DABCO (0.2 mmol, 1.0 equiv) in a neat condition under microwave (MW)
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b
c
irradiation at 70 °C in an open atmosphere. Isolated yield after column chromatography. 0.5
5
6
d
e
equiv DABCO was used in THF (0.5 mL). 1.0 equivalent of DABCO. 2.0 equivalent of
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DABCO.
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DABCO at 70 °C, the yield of 3aa was dramatically improved from 59% to 81% after 5h
(entry 3). However, no noticeable enhancement of yield (83%) of 3aa was observed when
the loading of DABCO was increased from 1.0 equiv. to 2.0 equiv. In order to make this
procedure more economical, practical and eco-friendly, we performed this domino
reaction in a neat condition under Microwave irradiation at 70 °C. Intriguingly, excellent
results were obtained in terms of yield 91% (3aa) and reaction time (20 min). Whereas,
by conventional heating at 70 °C, this domino reaction furnished a little lower yield
(85%) of 3aa with longer reaction time (2h, entry 5) in comparison to MW irradiation.
Moreover, the role of other organic bases like DBU, DIPEA, DMAP and triethylamine on
this domino reaction was also examined under MW irradiation. But all the bases were
appeared to be less effective as compared to DABCO, providing yields within the range
of 28 % to 55% (entries 7-10).
In keeping view of the above results,
a reasonable reaction mechanism has been
proposed for the formation of 3aa as depicted in Scheme 2. At the onset, DABCO may
abstract a methylene proton of cyclic sulfamidate imine to form a carbanion intermediate
1a'. Afterwards, the Michael addition reaction takes place between carbanion
intermediate 1a' and β,γ-unsaturated α-ketoester (2a) to generate the Michael adduct
which is subsequently underwent elimination of SO3 under the influence of base, leading
to a very reactive intermediate 5. The latter in turn converts into intermediate via an
4
6
iminocyclization, followed by dehydration which leads to the final product 3aa
.
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Scheme 2. Probable Mechanism for the Formation of Picolinate 3aa
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9
Et
CO2
O
Et
CO2
O
O
O
O
O
O
O
O
N
N
N
N
S
S
a
2
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13
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N
O
N
Ph
Ph
H
S
H
-
O
SO3
N
Ph
Ph
Ph
-
H
a'
c ae a
Mi h l dditi
on
a
1
1
4
Ph
O
H
O
Et
CO2
H
m noc c za on
i i
y li ti
N
NH
Et
CO2
-
H
Ph
2O
Ph
Et
O2C
N
aa
Ph
Ph
Ph
3
6
5
Having optimal reaction parameters in hand, we explored the generality and scope of this
solvent-free microwave-assisted domino reaction by involving numerous 4-
aryl/heteroaryl-substituted cyclic sulfamidate imines and γ-aryl/heteroaryl/alkyl-
substituted β,γ-unsaturated α-ketoesters in our optimal conditions to access a wide range
of substituted picolinate derivatives. The obtained results are systematically arranged in
Table 2. Not only phenyl but also aryl-substituted-β,γ-unsaturated α-ketoesters (2b-2h
)
bearing either electron-donating (OMe, OBn) or electron-withdrawing (F, Cl, Br, CF3,
CN, NO2) substituents on the aryl rings underwent a clean reaction with 1a under the
present conditions to provide corresponding 4,6-diarylpicolinates (3ab-3ah) in high to
excellent yields (83-93%) within 20-30 min. Pleasantly, attaching with bulky aryl-
substituents such as 2,6-dichlorophenyl (2i), 2,6-difluorophenyl (2j), biphenyl (2k) and
2-naphthyl (2l) at the γ-position of β,γ-unsaturated α-ketoesters did not make any
difficulty in the reaction with cyclic imine 1a to afford very high yields (84-88%) of the
corresponding picolinates (3ai-3al). Moreover, by using heteroaryl-substituted
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Table 2. Substrate Scope of 4,6-Disubstitutedpicolinate Synthesis (3aa-3ao)
R1
O
.
1 0
,
O
O
O
e
DAB
CO
q
(
)
S
-
°
,
,
nea
m n
i
MW 0 C
7
t 2
0 30
N
Et
O2C
+
R1
=
R
N
Et
CO2
R
-
-
-
a n
2
a
aa ao
1
i
3
3
=
=
=
=
=
=
=
a:
-
1
R
R
R
R
R
R
Ph
,
=
=
=
1
1
1
a:
:
R
e
2
2
2b
R
R
Ph
4 M
H4
:
OC6
,
-
-
:
1b
e
-
- -
-
4 M
H4
C6
10
11
12
13
14
15
16
17
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19
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22
23
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25
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=
1
c:
e:
e
n
2d
3 M
O
4 B
OC6
H3
=
1
R
4 F H4
C6
-
:
c
1
e
4 M
H4
OC6
-
,
1
r
:
2
2f
-
R
4 B H4
R
4 N
:
H4
C6
CC6
:
1d
4 F H4
C6
,
-
-
=
=
=
1
1
R1
,
4
N
H4
:
R
4
F
H4
=
:
-
2
2h
g R
O2 C6
C 3C6
:
e
1
4
2
l
l
r
ur
H4
C C6
-
-
-
-
,
,
,,
,
=
=
1
1
-
-
:
:
2k
2i
2
m
R
R
2 6
l
H3
,
2 6 F
H3
r
R
4 Ph H4
C6
C 2C6
2C6
:
j
1f
H4
C C6
-
-
-
=
1
,
=
1
1
n
:
R
:
2l
n
a
:
ur
2
2
2
phthyl
R
4 py idyl
2 f yl
:
1
g R 4 B H4
C6
-
=
1
=
=
o:
2
e
M
2C
R
H
:
1h
R
2 f yl
(
)
-
:
1i
o
e
n
R
2 thi ph yl
e
M
O
n
B
O
X
N
X
e
M
O
Ph
N
Ph
Et
CO2
Ph
Et
CO2
Ph
N
F
B
CO2Et
Ph
N
Et
Ph
N
E
t
CO2
,
CO2
,
,
=
,
,
=
=
a :
m n
20
a :
3
m n
m n
i
;
N
3 f X
a :
i
C
93%
3 d X
i
90 20
%
,
a :
3 b
m n
aa:
ac:
m n
m n
,
,
,
88 30
%
i
3
i
=
3
i
91 20
83% 30
%
ae:
r
m n
i
X
88 20
;
91 20
%
3 g
X
N
O2
%
Ph
F
C
3
l
C
l
C
F
F
Ph
N
Et
CO2
,
Ph
a :
N
Et
CO2
Ph
N
Et
CO2
,
Ph
N
a :
3 l
E
t
CO2
N
Et
CO2
m n
i
Ph
,
,
,
a :
3
m n
i
m n
i
:
a
h
a
:
3
i
m n
m n
i
3
k
7
8 %
86 20
%
88% 30
25
3
i
93 20
84 20
%
%
j
N
O
Ph
Ph
F
F
N
Et
m n
CO2
N
Et
CO2
N
Et
CO2
Ph
N
Et
m n
i
CO2
Ph
an:
N
Et
CO2
,
,
,
ca:
3
:
m n
m n
a:
,
3b
j
2
9 %
2
0
i
91 20
i
%
3b
i
,
90 20
%
m n
i
e
M
am:
3
3
8
4
%
30
e
M
e
82 30
%
M
O
e
M
O
N
Ph
Ph
N
N
Et
CO2
N
Et
CO2
N
Et
CO2
Et
CO2
N
t
CO2E
e
,
,
F
M
,
O
,
a:
3d
,
m n
i
:
m n
i
:
cm
3
m n
e :
3 l
m n
30
3db
85 30
%
8 %
F
1
30
F
83 20
i
l
C
ea:
3
m n
86 30
i
Cl
%
%
5
i
8
%
F
C
3
N
Ph
F
F
N
Et
N
:
Et
CO2
CO2
N
Et
CO2
N
Et
CO2
N
:
Et
CO2
O
O
r
B
l
C
l
C
,
,
,
,
,
a:
m n
85 30
%
m
m n
i
:
m n
i
3h
i
m n
m n
i
3h
j
3f
84 30
83 30
%
%
h;
3gd
7
8
i
3f
30
88 30
%
%
e
M
e
M
Ph
l
C
l
C
Ph
ao:
N
Et
CO2
N
,
Et
N
Et
CO2
CO2
S
S
3ii
,
,
:
m n
i
m n
0
4 i
a:
3i
m n
i
3
82 30
%
52
%
85 30
%
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(pyridyl and furyl) β,γ-unsaturated α-ketoesters (2m-2n), the domino reaction responded
elegantly in this imposed conditions and resulted in 82% yield of bipyridyl derivative
3am and 84% yield of 4-furylpicolinate 3an. Next, the effect of substitutions on the aryl
rings of cyclic sulfamidate imines was also taken under investigation. For instance, cyclic
sulfamidate imines (1d-1g) having halide atoms (F, Cl, Br) on the aryl rings slightly
diminished their reactivities towards β,γ-unsaturated α-ketoesters as compared to cyclic
sulfamidate imines (1b-c) bearing electron donating ones (Me, MeO). However, all the
cases led to high yields (81-92%) of the corresponding products (3ba-3gd). Gratifyingly,
heteroaryl-substituted cyclic imines 1h and 1i also afforded the corresponding products
3ha, 3hj, 3ia, and 3ii in 85%, 84%, 85%, and 82% chemical yields respectively.
Interestingly, by this procedure, γ-alkyl-substituted-βγ-unsaturated α-ketoester (2o) also
reacted with 1a to afford 4-alkylatedpicolinate 3ao in 52% yield after 40 min.
Importantly, a range of functionalities such as MeO, OBn, F, Cl, Br, CN, NO2, CF3,
CO2Et, furan, thiophene, pyridine etc. have been retained under this MW irradiation
conditions.
10
11
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15
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17
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19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In order to further investigate the possible substrate scope, the chemically challenging
Michael acceptors like γ-styryl-substituted α-ketoesters (2p-2r) were subjected to the
coupling reaction with several 4-aryl/hetero-substituted cyclic imines (1a-i).
Gratifyingly, under the MW irradiation, cyclic amines attacked only at the γ-position of
β,γ-unsaturated α-ketoesters. Consequently, all of the cyclization reactions delivered
consistently high to excellent yields (83-91%) of the corresponding 4-(E)-styryl-
substituted picolinates (3ap-3ip) after 20-30 min (Table 3).
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Table 3. Synthesis of (E)-6-Aryl-4-Styryl-Substituted Picolinates (3ap-3ip)
5
6
R1
O
7
8
9
O
O
O
.
E
t
CO2
,
S
e
1 0
q
)
DAB
CO
(
N
+
,
°
7
MW
m n
i
0 C
-
20 30
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
R
N
Et
CO2
R1
-
-
-
a
r
a
1
3 p 3ip
2p
i
e
M
O
Ph
Ph
N
O2
N
Et
CO2
Ph
N
Et
Ph
N
,
Et
CO2
CO2
Ph
N
Et
CO2
e
M
O
,
,
,
ar:
c
3 p
m n
i
m n
i
a :
3 q
m n
i
a :
3 p
3
m n
i
90 20
%
91 20
%
83 30
%
89
20
%
Ph
Ph
Ph
Ph
N
Et
CO2
N
Et
r
N
Et
CO2
CO2
N
,
Et
CO2
S
O
F
B
,
,
hp;
84 20
m n
i
;
3ip
m n
85 20
%
m n
i
,
3
;
i
3gp
%
85 20
%
m n
i
;
3dp
83 30
%
After successfully synthesizing styryl-substituted picolinate derivatives, we envisioned
that the synthesis of alkynyl-substituted picolinates under metal-free conditions may be
achieved by using γ-alkynyl α-ketoester as an appropriate Michael acceptor which is
traditionally followed through the Sonagashira cross-coupling reaction.22 In this line,
Scheme 3. Synthesis of 4-Phenylacetylenyl Picolinate Derivatives (3as-3is)
Ph
O
O
O
.
Et
CO2
e
0 q
)
t
30
DAB
CO
MW 7
0 C
1
S
(
°
,
,
,
nea
N
m n
i
+
O
R
R
N
Et
%
CO2
;
4 M
-
=
as:
s:
es:
s:
a
Ph
s
2
3
3b
3
3
3
R
R
R
R
Ph
8
5
OC6
1 i
-
=
=
=
e
;
H
80
%
4
-
-
;
H 86
C C6
%
4
4
l
ur
;
h
i
2 f yl
8
2
%
-
=
s:
o
en
;
R
2 hi ph yl
t
83
%
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γ-phenylacetylenyl-β,γ-unsaturated α-ketoester (2s) as was allowed to react with several
4-aryl/heteroaryl-substituted cyclic imines (1a-b, 1e, and 1h-i) under MW irradiation in
the presence of DABCO. Notably, all of the domino reactions took place exclusively at
the γ-position of β,γ-unsaturated α-ketoesters by this method which led to a range of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
anticipated 6-aryl/furyl/thiophenyl-4-phenylacetylenylpicolinates (3as-3is) in high yields
(80-86%, Scheme 3).
Furthermore, replacing β,γ-unsaturated α-ketoesters by other interesting Michael
acceptors namely β,γ-unsaturated α-ketobenzoyl (2t) and cinnamil (2u), they
participated efficiently in the reaction with several 4-aryl/heteroaryl-substituted cyclic
imines by our metal-free conditions. To our great pleasure, after 30-40 min, an
interesting class of trisubstituted pyridines (3at-3du) having a benzoyl or cinnamoyl
group at C-2 position were obtained in promising yields 77-86% as shown in Table 4.
Table 4. Synthesis of 4,6-Diaryl-2-Benzoyl/Cinnamoylpyridine Scaffolds (3at-3du)
O
.
Ph
O
O
e
0 q
)
DAB
CO
MW 7
0 C
1
O
O
(
-
S
°
,
,
,
nea
m n
4 i
t
30 0
N
+
R1
R1
R
N
Ph
R
R
-
=
-
1
a
3
u
O
:
=
t d
3
2t
R
Ph
:
1
j
r
B
C6
H4
3
=
1
u
2
:
r
s
ty yl
R
Ph
Ph
Ph
Ph
r
Ph
B
Ph
Ph
Ph
N
Ph
N
,
N
,
N
,
O
O
m n
O
O
O
e
O
M
:
t
3b
m n
i
,
a :
3
m n
85 30
%
:
t
3
j
m n
t
i
:
77
86 30
%
i
81 35
%
ht
3
i
30
%
Ph
Ph
Ph
Ph
Ph
Ph
N
N
Ph
N
O
S
O
O
,
F
,
,
u
:
m n
i
:
m n
i
3d
7
8
%
au:
3
40
m n
0
it
3
82 35
%
7
9
%
4
i
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Next, our motivation towards the metal-free access to synthetically challenging alkyl-
substituted picolinate derivatives has been successfully addressed by performing the
reaction of 5-methyl-4-phenyl cyclic sulfamidate imine (1k) with several aryl/hetero-
aryl/alkyenyl/alkynyl-substituted α-ketoesters (1a and 1b), furnishing acceptable yields
(41-58%, Table 5) of the corresponding tetrasubstituted pyridines having alkyl, alkenyl
and alkynyl groups on the pyridine rings. Therefore, the current methodology was not
restricted only for the synthesis of aryl-substituted pyridines but it could be also fairly
applicable for the access to non-arylated pyridine derivatives.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Synthesis of 5-Methyl-4,6-Disubstituted Picolinates (3ka-3ks)
.
e
0 q
)
R
N
DAB
CO
1
O
(
O
N
O
O
°
,
,
nea
MW
t
e
M
80 C
S
-
m n
Et
CO2
20 35
i
+
Ph
Et
CO2
R
e
M
Ph
-
=
v:
o
en
2
-
R
2 thi ph yl
1k
a
k
3
s
k
3
r
B
N
C
e
M
e
M
e
M
Ph
N
Et
CO2
m n
5
i
Ph
N
,
Et
CO2
m n
i
Ph
N
%
Et
Et
CO2
m n
4 i
0
,
,
:
e
k
:
a
k
:
3
4
3
3
44
3
%
k
3 f
45
30
%
Ph
Ph
S
e
M
e
M
e
M
Ph
N
Et
CO2
Ph
N
Ph
N
,
Et
CO2
CO2
m n
i
,
,
:
kp
v:
k
:
s
k
3
5
8
m n
i
m n
i
3
54 25
%
3
41
2
0
30
%
%
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For the further exploration of the designed methodology, we inspired to use a 4-alkyl-
benzo[e][1,2,3]oxathiazine 2,2-dioxide (1l) instead of a 5-membered cyclic imine as a
nucleophile for the first time, while reacting with a number of β,γ-unsaturated α-
ketoesters (2a-v) under MW irradiation at 80 °C. To our immense surprise, after 30-40
min, all of the reactions produced a fascinating class of several 6-(2-hydroxyphenyl)-4-
arylpicolinates 3la, 3lb, 3ld, and 3lv in 72%, 70%, 75% and 68% yields respectively
(Scheme 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Synthesis of 2-Hydroxyphenyl Substituted Picolinates (3la-3lv)
R1
.
e
0 q
)
O
DAB
CO
1
(
O
C
O
-
,
,
nea
m n
i
MW
t
4
30 0
S
O
+
R1
Et
N
Et
CO2
N
CO2
H
O
H
3
-
-
v
R
v
a
a
1l
2
2
3l 3l
=
=
=
=
=
1
1
1
1
a:
a:
l
;
Ph
3
3
3
3
R
Ph
7
2
%
-
-
=
=
=
:
e
:
:
:
e
2b
2d
v
;
7
0%
R
R
4 M
-
H4
OC6
lb
R
R
4 M
-
H4
OC6
1
1
:
:
;
4 F H4
ld
v
l
C6
4 F H4
7
5
C6
o
%
-
-
1
1
o
e
n
e
n
;
2
R
2 thi ph yl
R
2 hi ph yl
t
68
%
Next, we have demonstrated the potential synthetic utility of synthesized picolinate
derivative, the picolinate 3aa was successfully converted into a synthetically useful 4,6-
diphenyl-2-aminopyridine in 72% yield by two-step procedures. After that, the resultant
Scheme 5. Synthesis of Imidazo[1,2-a]pyridine Derivative (8)
N
O2
.
,
:
e
N H
C 2O
i Li H H
M
O
2O
)
Ph
u r
Ph
N
,
.
r
t 5h
e
B
1 q
C
0
(
)
Ph
Ph
,
,
,
°
o uene
ii DPPA Et N t l
DMF
80 C
)
3
,
°
a r
o
t 11
i 4h
65
0 C
Ph
8 7
N
Ph
N
7
NH2
Ph
N
E
t
CO2
e
y
i ld
aa
8
%
Ph
3
(
)
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2-aminopyridine derivative was subjected to the annulation reaction with β-nitrostyrene in
the presence of 10 mol% of CuBr in DMF at 80 °C for 4h to provide a biologically as
well as synthetically useful imidazo[1,2-a]pyridine derivative in 78% yield (Scheme
5).23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In this manuscript, we have developed first time a fast, general, expedient, environment-
friendly and MW-assisted domino reaction of different types of 5/6-membered cyclic
sulfamidate imines as useful Michael donors with
a
range of γ-
aryl/heteroaryl/alkenyl/alkynyl/alkyl-substituted-β,γ-unsaturated α-ketocarbonyls in a
neat condition promoted by DABCO. This unique Michael-elimination-cyclization (C-C
and C-N bonds formation) process furnishes a series of pharmaceutically relevant tri-and
tetra-substituted pyridines possessing a carboxylate, benzoyl or cinnamoyl group at C-2
position in high to excellent yields under metal-free conditions. Moreover, our present
method excludes the use of volatile organic solvents, expensive and toxic metal-salts,
strong acids, large excess of additional oxidants, multistep etc. In addition, the operational
simplicity, wider substrate scope, high to excellent yields, short reaction time,
compatibility with a variety of functional groups on aryl rings and environment-friendly
nature make this procedure a good alternative to the reported methods. Further efforts
towards more substrates as well as their applications in medicinal chemistry are under
progress which will be published in due course of time.
EXPERIMENTAL SECTION
General Information: All the cyclic sulfamidate imines (1a-j,24a 1k
and 1l
)
and β, γ-
24b
24c 24
unsaturated α-ketocarbonyls/cinnamil (2a-v)25 were synthesized by known literature procedures.
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All the catalysts were purchased from commercial sources. All the reactions were carried out
either under 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
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(200-300 mesh). FT-IR spectra were recorded on a KBr plate. H 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 = multiplet), coupling constant J
(Hz), integration, and assignment, data for 13C are reported as a chemical shift. High resolutions
mass spectral analyses (HRMS) were carried out using ESI-TOF-MS. Melting points were
recorded on an Electro thermal melting points apparatus and are uncorrected. All the microwave
irradiation reactions were carried out in a MILESTONE microwave oven apparatus (microwave
labstation, power 1150W) under open atmosphere.
Representative Procedure for the Synthesis of Ethyl 4,6-Diphenylpicolinate (3aa):
A mixture of compound 1a (39.4 mg, 0.2 mmol), 2a (44.9 mg, 0.22 mmol) and DABCO (22.4
mg, 0.2 mmol) in a 5 mL round bottom flask was placed inside the micro oven under stirring
(teflon-coated magnetic stir bar) condition. The reaction mixture was exposed to microwave
irradiation (1150 W) in an open atmosphere at 70 °C (temperature was monitored at the external
surface vessel using an in-built infrared sensor system) for 30 min. Upon completion of the
reaction, the crude mass was directly purified without any workup by column chromatography
over silica-gel using a mixture of EtOAc/hexane (1:4, v/v) to afford the desired product 4,6-
diphenylpicolinate (3aa) as a white solid (91%, 55.0 mg).
All the synthesized products in Table 2- 5 and Scheme 3-4 were followed the above procedure.
1
13
All the new products were characterized by their corresponding spectroscopic data (IR, H, C
NMR and HRMS).
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Ethyl 4,6-diphenylpicolinate (3aa):19 yield 92% (55.0 mg).
5
6
7
8
Ethyl 4-(4-methoxyphenyl)-6-phenylpicolinate (3ab):19 yield 88% (58.6 mg).
Ethyl 4-(4-(benzyloxy)-3-methoxyphenyl)-6-phenylpicolinate (3ac):19 yield 83% (72.9 mg).
Ethyl 4-(4-fluorophenyl)-6-phenylpicolinate (3ad): 19 yield 90% (57.8 mg).
Ethyl 4-(4-bromophenyl)-6-phenylpicolinate (3ae): white solid; yield 88% (67.2 mg); mp 106-
108 °C; Rf = 0.75 (EtOAc:hexane = 1:4); IR (KBr) ν 1715, 1605, 1545, 1493, 1434, 1372 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.10 (d, J = 6.8 Hz, 2H), 8.04 (s, 1H), 7.60-7.67 (m,
4H), 7.45-7.52 (m, 3H), 4.52 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.4, 158.5, 149.1, 149.0, 138.4, 136.6, 132.4, 129.5, 128.8, 128.6, 127.3 (2C), 121.1,
121.0, 62.0, 14.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H1679BrNO2Na 404.0257;
Found 404.0256; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H1681BrNO2Na 406.0237;
Found 406.0242.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 4-(4-cyanophenyl)-6-phenylpicolinate (3af):19 yield 93% (61.0 mg).
Ethyl 4-(4-nitrophenyl)-6-phenylpicolinate (3ag): light yellowish solid; yield 91% (63.4 mg);
mp 114-116 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr) ν 1733, 1592, 1551, 1513, 1430,
1
1346 cm-1; H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz, 2H), 8.28 (s, 1H), 8.09-8.13 (m,
3H), 7.90 (d, J = 8.8 Hz, 2H), 7.46-7.54 (m, 3H), 4.53 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 165.1, 158.7, 149.3, 148.3, 147.9, 143.9, 138.0, 129.8,
128.9, 128.2, 127.3, 124.4, 121.4, 121.3, 62.1, 14.3; HRMS (ESI-TOF) m/z: C21H16N2O4[M+H]+
Calcd for 349.1183; Found 349.1181.
Ethyl 6-phenyl-4-(4-trifluoromethylpheny)picolinate (3ah): white solid; yield 93 % (69.0
mg); mp 93-95 °C; Rf = 0.68 (EtOAc:hexane = 1:4); IR (KBr) ν 1735, 1596, 1550, 1463, 1429,
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1387 cm-1; H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.12 (d, J = 7.0 Hz, 2H), 8.08 (s, 1H),
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7.78-7.86 (m, 4H), 7.47-7.53 (m, 3H), 4.53 (d, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H); C
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NMR (100 MHz, CDCl3) δ 165.3, 158.6, 149.2, 148.9, 141.3, 138.3, 131.4 (q, JC-F = 32 Hz),
129.7, 128.9, 127.6, 127.3, 126.1 (q, JC-F = 4.0 Hz), 125.2 (q, JC-F = 270 Hz), 121.4 (2C), 62.0,
14.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C21H16F3NO2Na 394.1025; Found 394.1028.
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Ethyl 4-(2,6-dichlorophenyl)-6-phenylpicolinate (3ai): pale yellow solid; yield 84% (62.4
mg); mp 102-104 °C; Rf = 0.77 (EtOAc:hexane = 1:4); IR (KBr) ν 1735, 1600, 1551, 1463, 1427
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 2H), 7.97 (s, 1H), 7.82 (s, 1H), 7.42-
13
7.51 (m, 5H), 7.30-7.34 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 165.2, 158.0, 148.6, 146.6, 138.3, 136.5, 134.2, 130.2, 129.5, 128.8, 128.3,
127.3, 124.5, 124.4, 61.9, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H16Cl2NO2
372.0553; Found 372.0543.
Ethyl 4-(2,6-difluorophenyl)-6-phenylpicolinate (3aj): white solid; yield 86% (58.3 mg); mp
90-92 °C; Rf = 0.78 (EtOAc:hexane = 1:4); IR (KBr) ν 1739, 1626, 1597, 1546, 1469, 1423 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.09 (d, J = 7.6 Hz, 2H), 7.99 (s, 1H), 7.38-7.52 (m,
4H), 7.05-7.09 (m, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.2, 159.9 (d, JC-F = 250 Hz), 157.9, 148.5, 130.7 (t, JC-F = 10.0 Hz ), 129.5, 128.8 ,
127.3, 124.7 (d, JC-F = 22.0 Hz), 115.5 (t, JC-F = 18.0 Hz), 112.0, 111.9, 111.8, 61.9, 14.2; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C20H15F2O2NNa 362.0962; Found 362.0963.
Ethyl 4-[4-(1,1'-biphenyl)]-6-phenylpicolinate (3ak): light yellowish solid; yield 88% (66.6
mg); mp 110-112 °C; Rf = 0.78 (EtOAc:hexane = 1:4); IR (KBr) ν 1712, 1600, 1537, 1431, 1372
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.13-8.15 (m, 3H), 7.83-7.85 (m, 2H), 7.75-
7.77 (m, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.38-7.54 (m, 6H), 4.53 (q, J = 6.8 Hz, 2H), 1.50 (t, J =
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6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 158.3, 149.8, 149.0, 142.3, 140.0, 138.6,
136.4, 129.4, 128.9, 128.8, 127.8 (2C), 127.5, 127.3, 127.0, 121.2, 121.1, 61.9, 14.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C26H22NO2 380.1645; Found 380.1652.
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Ethyl 4-(2-naphthyl)-6-phenylpicolinate (3al): pale yellow solid; yield 87% (61.4 mg); mp
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86-88 °C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr) ν 1708, 1598, 1546, 1429, 1375 cm-1; H
NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.23 (d, J = 6.0 Hz, 2H), 8.16 (d, J = 7.6 Hz, 2H), 7.84-
13
8.01 (m, 4H), 7.45-7.58 (m, 5H), 4.54 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 165.6, 158.3, 150.2, 149.0, 138.6, 134.9, 133.5, 133.4, 129.4, 129.0, 128.8,
128.5, 127.7, 127.3, 127.0, 126.8, 126.7, 124.4, 121.6 (2C), 61.9, 14.3; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C24H20NO2 354.1489; Found 354.1486.
Ethyl 4-(4-pyridyl)-6-phenylpicoline (3am): white solid; yield 82% (49.8 mg); mp 88-90 °C;
Rf = 0.24 (EtOAc:hexane = 1:4); IR (KBr) ν 1719, 1594, 1537, 1457, 1427, 1372 cm-1; 1H NMR
(400 MHz, CDCl3): δ 8.82 (br s, 2H), 8.28 (s, 1H), 8.10-8.14 (m, 3H), 7.67 (br s, 2H), 7.47-54
(m, 3H), 4.53 (q, J = 6.8 Hz, 2H), 1.49 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.2,
158.8, 149.4, 147.6, 145.2, 138.1, 129.8 , 128.9 (2C), 127.3 (2C), 121.2 (2C), 62.1, 14.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C19H17N2O2 305.1285; Found 305.1288.
Ethyl 4-(2-furyl)-6-phenylpicolinate (3an):19 yield 84% (49.2 mg).
Ethyl 4-phenyl-6-(4-methylphenyl)picolinate (3ba):19 yield 90% (57.1 mg).
Ethyl 4-(2,6-difluorophenyl)-6-(4-methylphenyl)picolinate (3bj): light yellow solid; yield
91% (64.3 mg); mp 93-95 °C; Rf = 0.78 (EtOAc:hexane = 1:4); IR (KBr) ν 1738, 1622, 1602,
1
1544, 1469, 1414, 1367 cm-1; H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.92 (d, J = 8.0 Hz,
2H), 7.89 (s, 1H), 7.30-7.35 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.96-7.00 (m, 2H), 4.43 (q, J = 7.2
Hz, 2H), 2.34 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 159.9 (d, J
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= 250 Hz), 157.9, 148.4, 139,6, 139.2, 135.5, 130.6 (t, JC-F = 10 Hz), 129.5, 127.2, 124,5, 124.3,
115.6 (t, JC-F = 19 Hz), 112.0 (dd, J12 = 6 Hz, J13 = 20 Hz), 61.8, 21.2, 14.3; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C21H18F2O2N 354.1300; Found 354.1308.
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Ethyl 6-(4-methoxyphenyl)-4-phenylpicolinate (3ca): 19 yield 92% (61.3 mg).
Ethyl 4-(4-pyridyl)-6-(4-methoxyphenyl)picolinate (3cm): white solid; yield 83% (55.5 mg);
mp 100-102 °C; Rf = 0.20 (EtOAc:hexane = 1:4); IR (KBr) ν 1714, 1590, 1535, 1479, 1431,
1374 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 3.2 Hz, 2H), 8.21 (s, 1H), 8.09 (d, J = 8.4
Hz, 2H), 8.03 (s, 1H), 7.62 (d, J = 3.3 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 4.52 (q, J = 7.6 Hz, 2H),
3.88 (s, 3H), 1.48 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.2, 161.1, 158.3, 150.7,
149.2, 147.4, 145.3, 130.6, 128.6, 121.5, 120.4, 120.3, 114.2 (2C), 62.0, 55.3, 14.3; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C20H19N2O3 335.1390; Found 335.1378.
Ethyl 6-(4-fluorophenyl)-4-phenylpicolinate (3da):19 yield 85% (54.5 mg).
Ethyl 6-(4-fluorophenyl)-4-(4-methoxyphenyl)picolinate (3db): white solid; yield 81% (54.8
mg); mp 94-96 °C; Rf = 0.55 (EtOAc:hexane = 1:4); IR (KBr) ν 1712, 1604, 1546, 1511, 1433,
1369 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.08-8.12 (m, 2H), 7.99 (s, 1H), 7.70 (d,
J = 8.4 Hz, 2H), 7.16-7.20 (t, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H),
3.88 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 163.8 (d, JC-F = 252
Hz), 160.9, 157.2, 149.9, 148.9, 135.0, 129.8, 129.2, 129.1, 128.3, 120.6 (d, JC-F = 46 Hz) 115.7
(d, JC-F = 21 Hz), 114.7, 61.9, 55.4, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H19FO3N
352.1343; Found 352.1343.
Ethyl 6-(4-chlorophenyl)-4-phenylpicolinate (3ea): 19 yield 86% (58.0 mg).
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Ethyl 6-(4-chlorophenyl)-4-(2-naphthyl)picolinate (3el): white solid; yield 85% (65.9 mg); mp
104-106 °C; Rf = 0.72 (EtOAc:hexane = 1:4); IR (KBr) ν 1708, 1598, 1546, 1493, 1438 cm-1; 1H
NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 8.8 2H), 7.90-
8.01 (m, 3H), 7.84 (d, J = 8.0 Hz, 1H), 7.56-7.58 (m, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.54 (q, J =
7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 157.0, 150.3, 149.0,
137.0, 135.6, 134.6, 133.5, 133.3, 129.1, 128.9, 128.5, 128.4, 127.7, 127.0, 126.8, 126.7, 124.3,
121.8, 121.2, 62.0, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H19ClNO2 388.1099;
Found 388.1099.
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Ethyl 6-(2-chlorophenyl)-4-(4-trifluoromethylphenyl)picolinate (3fh):
yield 88% (71.3
mg).
Ethyl 4-(4-pyridyl)-6-(2-chlorophenyl)picolinate (3fm): white solid; yield 83% (56.2 mg); mp
104-106 °C; Rf = 0.24 (EtOAc:hexane = 1:4); IR (KBr) ν 1714, 1589, 1535, 1479, 1431, 1373
cm-1; 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.0 Hz, 2H), 8.36 (s, 1H), 8.09 (s, 1H), 7.73 (d,
J = 6.8 Hz, 1H), 7.63 (d, J = 2.4 Hz, 2H), 7.49-7.51 (m, 1H), 7.37-7.42 (m, 2 H), 4.53 (q, J = 7.2
13
Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 164.9, 157.9, 150.8, 149.4,
146.5, 144.7, 138.0, 132.1, 131.9, 130.2, 130.0, 127.2, 125.7, 121.4 (2 C), 62.1, 14.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C19H16ClN2O2 339.0895; Found 339.0878.
Ethyl 6-(4-bromophenyl)-4-(4-fluorophenyl)picolinate (3gd):19 yield 87% (69.5 mg).
Ethyl 6-(2-furyl)-4-phenylpicolinate (3ha): light yellow solid; yield 85% (49.8 mg); mp 78-80
°C; Rf = 0.68 (EtOAc:hexane = 1:4); IR (KBr) ν 1706, 1609, 1547, 1493, 1446, 1407, 1382 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.75 (d, J = 7.2 Hz, 2H), 7.48-7.57 (m,
4H), 7.26 (s, 1H), 6.57 (s, 1H), 4.51 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H); 13C NMR (100
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MHz, CDCl3) δ 165.3, 152.9, 150.2, 150.1, 148.9, 143.7, 137.3, 129.5, 129.1, 127.0, 121.0,
119.1, 112.2, 110.1, 61.9, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H16NO3 294.1125;
Found 294.1129.
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Ethyl 4-(2,6-difluorophenyl)-6-(2-furyl)picolinate (3hj): light yellow solid; yield 84% (55.3
mg); mp 81-83 °C; Rf = 0.70 (EtOAc:hexane = 1:4); IR (KBr) ν 1740, 1622, 1468, 1367 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 7.37-7.44 (m, 1H), 7.27
13
(s, 1H), 7.04-7.09 (m, 2H), 6.57 (s, 1H), 4.50 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 6.8 Hz, 3H); C
NMR (100 MHz, CDCl3) δ 164.9, 159.9 (d, JC-F = 250.0 Hz), 152.6, 149.8, 148.5, 143.8, 139.3,
130.8 (t, JC-F = 10.0 Hz), 124.3, 122.7, 115.3 (t, JC-F = 20 Hz), 112.2, 112.0 (dd, J1 = 6.0 Hz, J2 =
19.0 Hz), 110.3, 61.9, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H14F2NO3 330.0936;
Found 330.0933.
Ethyl 6-(2-thiophenyl)-4-phenylpicolinate (3ia): white solid; yield 85% (52.5 mg); mp 74-76
1
°C; Rf = 0.70 (EtOAc:hexane = 1:4); IR (KBr) ν 1709, 1597, 1544, 1443, 1371 cm-1; H NMR
(400 MHz, CDCl3) δ 8.18 (s, 1H), 7.97 (s, 1H), 7.71-7.75 (m, 3H), 7.44-7.55 (m, 4H), 7.13-7.15
(m, 1H), 4.50 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3,
153.4, 150.4, 148.8, 143.9, 137.5, 129.5, 129.2, 128.3, 128.0, 127.0, 125.6, 121.3, 119.7, 61.9,
14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H16O2NS 310.0896; Found 310.0898.
Ethyl 4-(2,6-dichlorophenyl)-6-(2-thiophenyl)picolinate (3ii): white solid; yield 83% (61.8
mg); mp 82-84 °C; Rf = 0.70 (EtOAc:hexane = 1:4); IR (KBr) ν 1739, 1600, 1548, 1435 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.61-7.62 (m, 2H), 7.37-7.40 (m, 2H), 7.23-7.27 (m,
1H), 7.18 (s, 1H), 7.04-7.07 (m, 1H), 4.41 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.9, 153.2, 148.5, 146.6, 143.7, 136.3, 134.1, 130.3, 128.5, 128.3, 128.1,
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125.9, 124.1, 122.8, 61.9, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H14Cl2NO2S
378.0117; Found 378.0108.
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(E)-Ethyl 4-isopropyl-6-phenylpicolinate (3ao): gummy liquid; yield 52% (28.0 mg), Rf = 0.78
(EtOAc:hexane = 1:4); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.92 (s, 1H), 7.73
(s, 1H), 7.42-7.49 (m, 3H), 4.48 (q, J = 7.2 Hz, 2H), 3.00-3.07 (m, 1H), 1.46 (t, J = 7.2 Hz, 3H),
1.33 (d, J = 3.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 165.9, 159.5, 157.8, 148.4, 138.9,
129.2, 128.7, 127.3, 121.9, 121.8, 61.8, 33.9, 23.1, 14.3; HRMS (ESI-TOF) m/z: [M+H]+Calcd
for C17H20NO2: 270.1489; Found 270.1485.
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(E)-Ethyl 6-phenyl-4-styrylpicolinate (3ap):19 Yield 89% (58.6 mg).
(E)-Ethyl 4-(4-methoxystyryl)-6-phenylpicolinate (3aq): light yellow solid; yield 83% (59.6
mg); mp 70-72 °C; Rf = 0.52 (EtOAc:hexane = 1:4); IR (KBr) ν 1723, 1676, 1608, 1514, 1456,
1
1375 cm-1; H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.88 (s, 1H),
7.38-7.53 (m, 6H), 7.00 (d, J = 16.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H),
3.85 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 160.4, 158.2, 148.7,
147.0, 138.8, 133.7, 129.3, 128.8, 128.7, 128.5, 127.3, 123.2, 120.6, 120.1, 114.3, 61.9, 55.4,
14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H22NO3 360.1594; Found 360.1609.
(E)-Ethyl 4-(2-nitrostyryl)-6-phenylpicolinate (3ar): white solid; yield 90% (67.3 mg); mp 76-
78 °C; Rf = 0.50 (EtOAc:hexane = 1:4); IR (KBr) ν 1711, 1600, 1515, 1435, 1345 cm-1; 1H NMR
(400 MHz, CDCl3) δ 8.15 (s, 1H), 8.04-8.11 (m, 3H), 7.91-7.76 (m, 2H), 7.76-7.79 (m, 1H),
7.66-7.69 (m, 1H), 7.45-7.51 (m, 4H), 7.09 (d, 16.0 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 1.48 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 158.4, 149.0, 148.0, 145.6, 138.3, 133.5,
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131.9, 130.5, 129.5, 129.3, 129.2, 128.8, 128.7, 127.2, 124.9, 120.8, 61.9, 14.3; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C22H19N2O4 375.1339; Found 375.1344.
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(E)-Ethyl 6-(4-methoxyphenyl)-4-styrylpicolinate (3cp): white solid; yield 91% (65.4 mg); mp
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78-80 °C; Rf = 0.53 (EtOAc:hexane = 1:4); IR (KBr) ν 1710, 1601, 1546, 1429, 1375 cm-1; H
NMR (400 MHz, CDCl3) δ 8.05-8.01 (m, 3H), 7.84 (s, 1H), 7.56-7.58 (m, 2H), 7.34-7.45 (m,
4H), 7.12 (d, J = 16.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 2H), 4.50 (q, J = 6.4 Hz, 2H), 3.87 (s, 3H),
1.48 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 160.8, 157.9, 148.6, 146.2, 135.9,
133.9, 131.2, 128.9, 1288, 128.5, 127.1, 125.6, 120.1, 119.6, 114.1, 61.8, 55.3, 14.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C23H22NO3 360.1594; Found 360.1594.
(E)-Ethyl 6-(4-fluorophenyl)-4-styrylpicolinate (3dp): light yellow solid; yield 83% (57.6
mg); mp 91-93 °C; Rf = 0.75 (EtOAc:hexane = 1:4); IR (KBr) ν 1714, 1601, 1549, 1510, 1437,
1370 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.09-8.11 (m, 2H), 7.86 (s, 1H), 7.58 (d,
J = 7.0 Hz, 2H), 7.35-7.43 (m, 4H), 7.12-7.20 (m, 3H), 4.51 (q, J = 6.8 Hz, 2H), 1.48 (t, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 163.8 (d, JC-F = 250.0 Hz), 157.2, 148.8, 146.7,
135.8, 134.8, 134.2, 129.1, 129.0, 128.9, 127.1, 125.3, 120.4 (d, JC-F = 46.0 Hz), 115.8, 115.6,
61.9, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H19NO2F 348.1394; Found 348.1391.
(E)-Ethyl 6-(4-bromophenyl)-4-styrylpicolinate (3gp):19 yield 85% (69.4 mg).
(E)-Ethyl 6-(2-furyl)-4-styrylpicolinate (3hp): gummy liquid; yield 84% (53.6 mg); Rf = 0.67
(EtOAc:hexane = 1:4); IR (KBr) ν 1714, 1608, 1546, 1493, 1370 cm-1; H NMR (400 MHz,
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CDCl3) δ 8.06 (s, 1H), 7.89 (s, 1H), 7.54-7.58 (m, 3H), 7.34-7.45 (m, 4H), 7.22 (s, 1H), 7.09 (d,
J = 16.4 Hz, 1H), 6.55 (s, 1H), 4.50 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 165.3, 152.9, 150.1, 148.7, 146.5, 143.6, 135.8, 134.2, 129.0, 128.9, 127.1,
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125.2, 120.0, 118.5, 112.2, 109.9, 62.0, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C20H18NO3 320.1281; Found 320.1276.
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(E)-Ethyl 6-(2-thiophenyl)-4-styrylpicolinate (3ip): gummy liquid; yield 85% (57.0 mg); Rf =
0.70 (EtOAc:hexane = 1:4); IR (KBr) ν 1737, 1713, 1635, 1593, 1544, 1494, 1443, 1369 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.79 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.57 (d, J =
7.2 Hz, 2H), 7.33-7.44 (m, 5H), 7.07-7.14 (m, 2H), 4.49 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 153.3, 148.6, 146.5, 143.9, 135.8, 134.2, 129.0,
128.8, 128.1, 128.0, 127.1, 125.5, 125.1, 119.9, 119.2, 61.9, 14.2; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C20H17NO2SNa 358.0872; Found 358.0877.
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Ethyl 6-phenyl-4-(phenylethynyl)picolinate (3as): white solid; yield 85% (55.6 mg); mp 98-
100 °C; Rf = 0.75 (EtOAc:hexane = 1:4); IR (KBr) ν 1721, 1596, 1540, 1455, 1426, 1372 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.01-8.05 (m, 3H), 7.91 (s, 1H), 7.50-7.52 (m, 2H), 7.38-7.44 (m,
3H), 7.32-7.36 (m, 3H), 4.43 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.0, 157.9, 148.5, 137.9, 133.3, 131.9, 129.6, 129.4, 128.8, 128.5, 127.2, 125.1 (2C),
121.9, 94.7, 86.4, 61.9, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H18NO2 328.1332;
Found 328.1334.
Ethyl 6-(4-methoxyphenyl)-4-(phenylethynyl)picolinate (3bs): light yellow solid; yield 80%
(57.1 mg); mp 108-110 °C; Rf = 0.53 (EtOAc:hexane = 1:4); IR (KBr) ν 1736, 1599, 1513, 1370
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cm-1; H NMR (400 MHz, CDCl3) δ 8.05-8.07 (m, 3H), 7.92 (s, 1H), 7.57-7.59 (m, 2H), 7.39-
7.42 (m, 3H), 7.01 (d, J = 8.0 Hz, 2H), 4.49 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.47 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 165.1, 161.0, 157.4, 148.3, 133.0, 131.9, 130.5, 129.3,
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128.5 (2C), 124.3, 124.2, 121.9, 114.1, 94.4, 86.5, 61.8, 55.3, 14.3; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C23H19NO3Na 380.1257; Found 380.1258.
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Ethyl 6-(4-chlorophenyl)-4-(phenylethynyl)picolinate (3es): white solid; yield 86% (62.2 mg);
mp 102-104 °C; Rf = 0.77 (EtOAc:hexane = 1:4); IR (KBr) ν 1714, 1595, 1534, 1490, 1419 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H), 7.57-7.59 (m,
2H), 7.45 (d, J = 8.0 Hz, 2H), 7.37-7.41 (m, 3H), 4.48 (d, J = 6.8 Hz, 2H), 1.46 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 164.8, 156.6, 148.6, 136.3, 135.9, 133.5, 131.9, 129.5,
129.0, 128.6, 128.5, 125.3, 124.8, 121.7, 95.0, 86.2, 62.0, 14.3; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C22H17ClNO2 362.0942; Found 362.0966.
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Ethyl 6-(2-furyl)-4-(phenylethynyl)picolinate (3hs): white solid; yield 82% (52.0 mg); mp 83-
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85 °C; Rf = 0.65 (EtOAc:hexane = 1:4); IR (KBr) ν 1712, 1606, 1542, 1511, 1435 cm-1; H
NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.93 (s, 1H), 7.55-7.58 (m, 3H), 7.40-7.43 (m, 3H), 7.23
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(s, 1H), 6.56 (s, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 164.8, 152.4, 149.8, 148.5, 143.9, 133.3, 131.9, 129.4, 128.5, 124.7, 123.0, 121.8,
112.2, 110.5, 94.9, 86.2, 62.0, 14.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H15NO3Na
340.0944; Found 340.0925.
Ethyl 6-(2-thiophenyl)-4-(phenylethynyl)picolinate (3is): white solid; yield 83% (55.3 mg);
mp 90-92 °C; Rf = 0.72 (EtOAc:hexane = 1:4); IR (KBr) ν 1709, 1594, 1534, 1441, 1373 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.58-7.60 (m, 2H), 7.41-
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7.46 (m, 4H), 7.14 (s, 1H), 4.48 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl3) δ 164.7, 153.0, 148.4, 143.3, 133.3, 132.0, 129.4, 128.6, 128.5, 128.1, 125.9,
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124.8, 123.4, 121.7, 94.9, 86.2, 62.0, 14.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C20H15NO2SNa 356.0716; Found 356.0719.
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2-Benzoyl-4,6-diphenylpyridine (3at): white solid; yield 86% (57.6 mg); mp 76-78 °C; Rf =
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0.75 (EtOAc:hexane = 1:4); IR (KBr): ν 1663, 1591, 1538, 1494, 1445 cm-1; H NMR (400
MHz, CDCl3) δ 8.23-8.27 (m, 3H), 8.15 (s, 1H), 8.10 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 7.6 Hz,
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2H), 7.61-7.64 (m, 1H), 7.45-7.56 (m, 8H); C NMR (100 MHz, CDCl3) δ 193.8, 156.7, 155.4,
150.5, 138.6, 138.0, 136.5, 132.8, 131.3, 129.4 (2C), 129.2, 128.8, 128.0, 127.2, 127.0, 121.0,
120.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H18NO 336.1383; Found 336.1387.
2-Benzoyl-4-phenyl-6-(4-methoxyphenyl)pyridine (3bt): light yellow solid; yield 85% (62.0
mg); mp 84-86 °C; Rf = 0.55 (EtOAc:hexane = 1:4); IR (KBr) ν 1658, 1593, 1541, 1507, 1453,
1418 cm-1; H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.6 Hz, 2H), 8.16 (s, 1H), 8.05-8.08 (m,
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3H), 7.77 (d, J = 7.2 Hz, 2H), 7.60-7.64 (m, 1H), 7.47-7.56 (m, 5H), 7.00 (d, J = 8.4 Hz, 2H),
3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.9, 160.8, 156.3, 155.3, 150.4, 138.1, 136.6,
132.8, 131.3, 131.2, 129.3, 129.2, 128.4, 128.0, 127.2, 120.3, 119.7, 114.2, 55.4; HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C25H19NO2Na 388.1308; Found 388.1311.
2-Benzoyl-4-phenyl-6-(3-bromophenyl)pyridine (3jt): white solid; yield 81% (66.9 mg); mp
94-96 °C; Rf = 0.76 (EtOAc:hexane = 1:4); IR (KBr) ν 1658, 1590, 1537, 1484, 1445, 1415 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.21 (m, 3H), 8.1 (s, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.77 (d, J =
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7.2 Hz, 2H), 7.62-7.66 (m, 1H), 7.52-7.56 (m, 6H), 7.34-7.38 (m, 1H); C NMR (100 MHz,
CDCl3) δ 193.5, 155.4, 155.0, 150.8, 140.6, 137.7, 136.3, 132.9, 132.3, 131.3, 130.4, 130.2,
129.6, 129.3, 128.0, 127.2, 125.6, 123.1, 121.4, 120.5; HRMS (ESI-TOF) m/z: Calcd for
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C24H1779BrNO[M+H]+ 414.0489; Found 414.0501. HRMS (ESI-TOF) m/z: Calcd for
C24H1781BrNO[M+H]+ 416.0468; Found 416.0517.
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2-Benzoyl-4-phenyl-6-(2-furyl)pyridine (3ht): white solid; yield 77% (50.1 mg); mp 72-74
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°C; Rf = 0.66 (EtOAc:hexane = 1:4); IR (KBr) ν 1660, 1606, 1541, 1492, 1446 cm-1; H NMR
(400 MHz, CDCl3) δ 8.24 (d, J = 7.6 Hz, 2H), 8.13 (s, 1H), 8.10 (s, 1H), 7.78 (d, J = 7.2 Hz,
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2H), 7.74-7.63 (m, 7H), 7.09 (d, J = 3.0 Hz, 1H), 6.55 (s, 1H); C NMR (100 MHz, CDCl3) δ
193.3, 155.3, 153.3, 150.3, 148.8, 143.6, 137.6, 136.3, 132.9, 131.4, 129.5, 129.2, 128.0, 127.1,
120.4, 118.2, 112.2, 109.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H16NO2 326.1176;
Found 326.1176.
2-Benzoyl-4-phenyl-6-(2-thiophenyl)pyridine (3it): light green solid; yield 82% (55.9 mg); mp
78-80 °C, Rf = 0.72 (EtOAc:hexane = 1:4); IR (KBr) ν 1654, 1587, 1541, 1500, 1438, 1359 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 7.2 Hz, 2H), 8.17 (s, 1H), 8.01 (s, 1H), 7.71-7.77 (m,
3H), 7.61-7.65 (m, 1H), 7.51-7.54 (m, 5H), 7.42 (d, J = 4.0 Hz, 1H), 7.14 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 192.9, 155.0, 151.9, 150.5, 144.4, 137.7, 136.2, 132.8, 131.5, 129.5, 129.2,
128.3, 128.2, 127.9, 127.1, 125.2, 120.7, 118.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H16NOS 342.0947; Found 342.0942.
2-Cinnamoyl-4,6-diphenylpyridine (3au): white solid; yield 79% (57.0 mg); mp 108-110 °C;
Rf = 0.77 (EtOAc:hexane = 1:4); IR (KBr) ν 1677, 1596, 1543, 1496, 1452 cm-1; H NMR (400
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MHz, CDCl3): δ 8.51 (d, J = 16.0 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J = 7.6 Hz, 2H), 8.15 (s, 1H),
8.03 (d, J = 16.0 Hz, 1H), 7.76-7.80 (m, 4H), 7.44-7.59 (m, 9H); 13C NMR (100 MHz, CDCl3) δ
189.7, 157.2, 154.6, 150.5, 144.6, 138.8, 137.9, 135.3, 130.5, 129.5, 129.4, 129.2, 128.9 (2C),
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128.8, 127.2, 127.1, 121.4, 121.2, 119.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20NO
362.1539; Found 362.1543.
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2-Cinnamoyl-4-phenyl-6-(4-fluorophenyl)pyridine (3du): white solid; yield 78% (59.1 mg);
mp 114-116 °C; Rf = 0.78 (EtOAc:hexane = 1:4); IR (KBr) ν 1672, 1600, 1509, 1449, 1414 cm-1;
1H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 16.0 Hz, 1H), 8.37 (s, 1H), 8.18-8.21 (m, 2H), 8.09
(s, 1H), 8.01 (d, J = 16.0 Hz, 1H), 7.75-7.79 (m, 4H), 7.45-7.56 (m, 6H), 7.23-7.27 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 189.6, 163.9 (d, JC-F = 250 Hz), 150.6, 144.8, 137.9, 135.3, 134.9 (2
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C), 130.6, 129.4, 129.2, 129.0, 128.9, 128.8, 127.2, 121.2, 121.1, 121.0, 119.3, 115.9 (d, JC-F
=
19 Hz); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H19NOF 380.1445; Found 380.1443.
Ethyl 5-methyl-4,6-diphenylpicolinate (3ka): white solid; yield 44% (27.9 mg); mp 86-88 °C;
Rf = 0.65 (EtOAc:hexane = 1:4); IR (KBr) ν 1712, 1580, 1545, 1499, 1448, 1384 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.97 (s, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.37-7.50 (m, 8H), 4.46 (q, J = 7.2
13
Hz, 2H), 2.25 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 165.5, 160.3,
151.6, 145.3, 140.4, 139.2, 132.6, 129.4, 128.7, 128.5, 128.2, 128.1 (2 C), 124.5, 61.7, 18.5,
14.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C21H19NO2Na 340.1308; Found 340.1309.
Ethyl 4-(4-bromophenyl)-5-methyl-6-phenylpicolinate (3ke): light yellow solid; yield 43%
(34.0 mg); mp 108-110 °C; Rf = 0.66 (EtOAc:hexane = 1:4); IR (KBr) ν 1714, 1594, 1542, 1488,
1448 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 6.8
Hz, 2H), 7.40-7.47 (m, 3H), 7.26 (d, J = 8.0 Hz, 2H), 4.46 (q, J = 6.8 Hz, 2H), 2.24 (s, 3H), 1.41
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 160.4, 150.4, 145.5, 140.1, 138.0,
132.4, 131.8, 130.4, 129.3, 128.3, 128.2, 124.2, 122.6, 61.8, 18.5, 14.3; HRMS (ESI-TOF) m/z:
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[M+H]+ Calcd for C21H1979BrNO2 396.0594; Found 396.0585. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C21H1981BrNO2 398.0574; Found 398.0568.
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Ethyl 4-(4-cyanophenyl)-5-methyl-6-phenylpicolinate (3kf): white solid, yield 45% (30.8 mg);
mp 100-102 °C; Rf = 0.53 (EtOAc:hexane = 1:4); IR (KBr) ν 1711, 1636, 1578, 1543, 1502,
1449 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.79 (d, J = 8.4 2H), 7.42-7.57 (m, 7H),
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4.47 (q, J = 6.8 Hz, 2H), 2.23 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ
165.2, 160.6, 149.6, 145.7, 143.8, 139.9, 132.4, 132.1, 129.6, 129.3, 128.5, 128.3, 123.9, 118.3,
112.4, 61.9, 18.4, 14.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H18N2O2Na 365.1260;
Found 365.1269.
Ethyl 4-(2-thiophenyl)-5-methyl-6-phenylpicolinate (3kv): light green solid; yield 41% (26.5
mg); mp 92-94 °C; Rf = 0.62 (EtOAc:hexane = 1:4); IR (KBr) ν 1709, 1578, 1542, 1443, 1372
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cm-1; H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.55 (d, J = 6.8 Hz, 2H), 7.39-7.48 (m, 4H),
7.26-7.27 (m, 1H), 7.15-7.17 (m, 1H), 4.46 (q, J = 6.8 Hz, 2H), 2.43 (s, 3H), 1.41 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 160.7, 145.5, 144.0, 140.3, 139.8, 132.6, 129.4,
128.4, 128.3, 128.2, 127.6, 127.3, 124.5, 61.8, 19.1, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C19H18NO2S 324.1053; Found 324.1056.
(E)-Ethyl 5-methyl-6-phenyl-4-styrylpicolinate (3kp): white solid; yield 54% (37.0 mg); mp
102-104 °C; Rf = 0.65 (EtOAc:hexane = 1:4); IR (KBr) ν 1712, 1627, 1576, 1540, 1446, 1392
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.51-7.54 (m, 2H),
7.33-7.47 (m, 5H), 7.35 (d, J = 7.2 Hz, 1H), 7.31-7.33 (m, 2H), 4.48 (q, J = 7.2 Hz, 2H), 2.42 (s,
13
3H), 1.44 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 165.8, 160.2, 145.8, 145.5, 140.3,
29
ACS Paragon Plus Environment