Domino reaction of cyclic sulfamidate imines with Morita-Baylis-Hillman acetates promoted by DABCO: a metal-free approach to functionalized nicotinic acid derivatives

Article abstract of DOI:10.1039/c7ob00240h

A facile, green, metal-free new one-pot synthetic strategy has been developed for easy access to a wide array of medicinally promising functionalized pyridines having an ester, a nitrile or an acetyl group at the C-3 position in good to excellent yields via a domino S_N2/elimination/6π-aza-electrocyclization/aromatization reaction of several 4-aryl/hetero-aryl-substituted 5-membered cyclic sulfamidate imines with a broad range of MBH acetates of acrylate/acrylonitrile/MVK in 2-MeTHF promoted by DABCO as an organobase under an O₂ atmosphere. Moreover, a biologically interesting triazolopyridine derivative was achieved through a unique procedure.

Full text of DOI:10.1039/c7ob00240h

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Domino reaction of cyclic sulfamidate imines with Morita-Baylis-
Hillman acetates promoted by DABCO: a metal-free approach to
functionalized nicotinic acid derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Debashis Majee, Soumen Biswas, Shaikh M. Mobin and Sampak Samanta*
DOI: 10.1039/x0xx00000x
A facile, green, metal-free based new one-pot synthetic strategy has been developed for the easy access to a wide array
of medicinally promising functionalized pyridines having an ester, nitrile or acetyl group at the C-3 position in good to
excellent yields via a domino SN2/elimination/6π-aza-electrocyclization/aromatization reaction of several 4-aryl/hetero-
aryl-substituted 5-membered cyclic sulfamidate imines with a broad range of MBH acetates of acrylate/acrylonitrile/MVK
www.rsc.org/
in 2-MeTHF promoted by DABCO as an organobase under O2 atmosphere. Moreover,
triazolopyridine derivative was achieved through
a
biologically interesting
a
unique procedure.
use of expensive metalꢀsalts and strong acids, lack of generality,
poor chemical yields with multiple byꢀproducts, harsh reaction
conditions, multiꢀsteps etc are major drawbacks of the aforesaid
protocols. To bypass the above difficulties, the development of a
simple, efficient, more flexible (structural diversity), metalꢀfree
based new synthetic technique for the construction of an interesting
functionalized nicotinic acid derivatives from simple substances
remains an industrial as well as an academic challenge.
On the other hand, we also reported a novel oneꢀpot protocol for the
synthesis of 4,6ꢀdiarylpicolinates via a domino SN2' additionꢀ
elimination sequence reaction of cyclic sulfamidate imines as
nucleophiles with MBH acetates of nitroolefins using DABCO
as an organobase (Scheme 1b).8 With this background, it is quite
reasonable to envisage that in order to access a similar kind of
pyridine derivative, well known nucleophilic acceptor like βꢀ
unsubstituted MBH acetate of acrylate 9 may be employed instead of
βꢀsubstituted MBH acetate of nitroolefin in the domino reaction with
cyclic sulfamidate imine which may proceed via a SN2 manner,
Introduction
Efficient construction of polyꢀfunctionalized pyridine containing an
ester, nitrile or acetyl group at Cꢀ3 position (as surrogate of
nicotinic acid or niacin or vitamin B3) is a key research topic in
chemical science.1 Importantly, this evergreen azaꢀheterocycle as
well as its nicotinic acid frameworks constitute several marketable
drugs,1b,e biologically active natural products,1cꢀe pharmaceuticals,2
agrochemicals,3 functional materials,4 and ligands for catalysis.5
Owing to their vast applications including the treatment of human
health, several chemists have been devoted towards the efficient
preparation of nicotinic acid derivatives by adopting several modern
techniques.1, 6ꢀ7 For example, Bohlman–Rahtz,6a Bagley and other
6bꢀe
groups
have independently developed general and powerful
synthetic strategies for the access to nicotinic acid derivatives by
involving the βꢀenaminoesters (or in situ generated βꢀenaminoesters
from βꢀketoesters and ammonium acetate) and alkynones catalysed
by several Brønsted and Lewis acids, or assisted by microwave
irradiation. Alternatively, the acid catalyzed complete regioselective
multicomponent reaction for the oneꢀpot synthesis of polyꢀ
substituted nicotinates from simple 1,3ꢀdicarbonyl compounds,
β,γꢀunsaturatedꢀαꢀketo esters and ammonium acetate was realized
by the Rodriguez group.7aꢀc Furthermore, Kim et al. also developed
the twoꢀstep synthetic methods for the preparation of nicotinate
derivatives using MoritaꢀBaylisꢀHillman (MBH) acetates of methyl
vinyl ketone (MVK) as bielectrophiles (Scheme 1a).7o Despite
spectacular advances on the synthesis of nicotinic acid derivatives,
leading
to
the
nicotinic
acid
derivative.
Scheme 1. Various synthetic approaches for pyridine synthesis using MBH
acetate adducts.
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As a part of our continued research interest involving cyclic 8). Considering the yield (82%, entry 3) and environment benign
sulfamidate imine as a nucleophile for various transformations,10 nature of 2ꢀMeTHF, it was chosen as the best solvent for this
herein we are pleased to report an interesting domino reaction of conversion. It should be noted that a mediocre yield (56%, entry 5)
several cyclic sulfamidate imines with different types of arylꢀ of 3aa was obtained when the same reaction was carried out under
substituted MBH acetates bearing ester/nitrile/acetyl groups in 2ꢀ open atmosphere instead of O2 balloon. Next, several common
MeTHF as an ecoꢀfriendly solvent promoted by DABCO to afford a organic bases namely DBU, DMAP, DIPEA, Et3N and quinine were
novel
series
of
4,6ꢀdiarylnicotinates/nicotinonitriles/3ꢀ tested for this domino reaction at 70 °C for 60 h. Surprisingly, all
these bases led to unsatisfactory results (5ꢀ52% yields of 3aa,
acetylpyridines (Scheme 1c).
entries 12ꢀ16) as compared to DABCO (82%, 48h, entry 3).
Results and Discussion
O
O
O
N
O
O
O
N
N
S
S
N
OAc
Ph
SN2
base
EtO2C
Table 1. Optimization of reaction conditions.a
Ph
EtO2C
H
Ph
Ph
1a
1a
Ph
O
O
S
2a
Ph
SN2
attack
O
N
N
OAc
CO2Et
N
O
O
attack
Ph
N
CO2Et
AcO
N
S
S 2-adduct
5
N
EtO2C
+
Conditions
isolated
4
Ph
N
O
Ph
Ph
Ph
N
3aa
EtO2C
EtO2C
CO2Et
O2
oxidation
Ph
elimination
-SO3
NH
Ph
1a
2a
6 -aza-
electrocylization
N
H
N
Ph
Ph
Ph
Entry
Ease
Solvent
Temp
(°C)
Time(h)
Yield
6
3aa
(%)b
10
52
82
83
56
79
74
59
33
27
21
5
7
isolated its N-Boc form 8
1
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
THF
rt
60
60
48
48
48
48
48
48
48
48
48
60
60
60
60
60
Scheme 2. Possible mechanism of this domino reaction.
2
45
70
70
70
70
70
70
70
70
70
70
70
70
70
70
According to the above reaction results,
a reasonable
3
4c
5d
6
mechanism of this domino reaction has been presented in
Scheme 2. At first, DABCO may attack at the βꢀposition of
MBH acetate 2a in a SN2' manner to form a reactive
The latter is nucleophilically (SN2')
attacked by carbanion intermediate 1a' (generated from 1a
under basic conditions) to give an isolable SN2 adduct in a
allylammonium salt 4 9
.
7
toluene
8
EtOAc
5
9
DMSO
nonꢀseparable mixture of diastereomer (dr = 3:1). The latter
undergoes elimination of SO3 under the influence of base to
10
11
12
13
14
15
16
DMF
EtOH
form an azaꢀtriene intermediate
dihydropyridine (isolated in its NꢀBoc protected form
experimental section) through a 6πꢀazaꢀelectrocyclization
process.7jꢀm Finally, the product 3aa is generated from
through aromatization under O2 atmosphere
6
which in turn converts to 1,2ꢀ
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
7
8
, see
DIPEA
<8
41
32
52
7
DMAP
.
Et3N
Quinine
Under the above optimal reaction conditions, several 4ꢀ
aryl/heteroarylꢀsubstituted cyclic sulfamidate imines 1a-i
have been used as nucleophiles in the oneꢀpot reaction with a
diverse range of aryl/styrylꢀsubstituted MBH acetates of
aReaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), base
(0.3 mmol) in solvent (1.0 mL) were heated at specified
temperature under O2 atmosphere. bIsolated yield. cDABCO
(2.5 equiv.). dOpen air.
(
)
acrylate
(2a-k) to evaluate the scope and generality of this
reaction. As shown in Table 2, incorporation of the electron
donating (Me, OMe, OBn) groups on the aryl rings of MBH
acetates (2b-c) lowered their reactivities towards 1a (48ꢀ72h
vs 36ꢀ40h) as compared to the electron withdrawing ones such
as F, Cl, Br, CF3, CN and NO2. However, all of the reactions
afforded typically high yields (77ꢀ87%) of 4,6ꢀdiarylnicotinates
By using 4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazoleꢀ2,2ꢀdioxide (1a) and MBH
acetate of acrylate (2a) as the test substrates, the reaction was
carried out in 2ꢀMeTHF as a green solvent at room temperature in
the presence of 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO, 1.5 equiv)
as an organobase under O2 atmosphere. Interestingly, after 60h, we
were able to isolate a trace amount of an important class of 4,6ꢀ
diarylnicotinate (3aa) in 10% yield (entry 1, Table 1). Gratifyingly,
on increasing the reaction temperature from 45 °C to 70 °C,
significant yield of 3aa was enhanced from 52% to 82% after 48h
(entries 2ꢀ3). This breakthrough result promoted us to investigate
the above unprecedented domino reaction in various common
organic solvents. Results clearly indicated that the polar solvents
namely DMSO, DMF and EtOH led to poor yields (21ꢀ33% , entries
9ꢀ11) of 3aa as compared to the nonꢀpolar ones (59ꢀ79%, entries 6ꢀ
(
3ab-3aj, ORTEP data of 3ai, ESI). Moreover, the cyclic
sulfamidate imines (1b-h) possessing both electron rich (Me,
OMe) and electron poor (F, Cl, Br) functionalities on the aryl
nuclei attacked MBH acetates (2a-j
)
in a SN2 manner,
resulting in good to high yields (74ꢀ86%) of the corresponding
nicotinates (3ba-3hg). It is noted that electron withdrawing
functionalities (e.g. F, Cl, Br) reduce the nucleophilicities of
cyclic sulfamidate imines, thus slowing the rates of the
reactions (48ꢀ60h). Pleasantly, the cyclic imines having
2 | J. Name., 2012, 00, 1-3
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heteroarylꢀsubstituents (1i-g) such as thiophene (1i)/furan (1g
)
thiophene, furan etc. were unaltered in the present mild
also proceeded very well with a variety of MBH acetates conditions. Furthermore, this protocol offers an easy entry to
under the present conditions which led to satisfactory unsymmetrically substituted nicotinates, in contrast to the
chemical yields (70ꢀ77%) of 6ꢀheteroarylꢀsubstituted traditional Hantzsch pyridine synthesis which affords
nicotinates (3ia-3jg). Notably, chemically challenging alkenyl substituted symmetrical pyridines.11
MBH acetate 2k was also found to be suitable substrate for the
domino reaction with 1a, leading to good yield (67%) of 4ꢀ After successfully developing a simple metalꢀfree based oneꢀ
styrylꢀ6ꢀphenylnicotinate
(
3ak).
Moreover,
several pot synthesis of 4,6ꢀdiarylnicotinates, we then applied the same
synthetically useful functionalities such as Me, OMe, OBn, F, procedure for the preparation of synthetically challenging12 4,6ꢀ
Cl, Br, CF3, NO2, CN, CO2Et, CO2Me,
diarylnicotinonitriles by involving the arylꢀsubstituted MBH
acetates derived from an acrylonitrile as reactive electrophiles.
The obtained results in Table 3 demonstrated that regardless of
the nature of the substituents (Me, OMe, OBn, F, Cl, Br, CF3)
and their positions on the arylꢀrings of MBH adducts (2l-s),
they underwent spotless reactions with a diverse range of arylꢀ
substituted cyclic imines (1a-h) under established conditions,
providing consistently high to excellent yields (80ꢀ90%) of the
corresponding 4,6ꢀdiarylnicotinonitriles (3al-3hs, surrogates of
nicotinic acid) after 12ꢀ24h. Moreover, this one–pot operation
was not limited only for arylꢀsubstituted cyclic imines 1a-h, but
it could be also equally applicable for heteroarylꢀsubstituted
cyclic imine. For instance, good yields (75ꢀ80%) of 6ꢀ
Table 2. Substrate scope of 4,6ꢀdiarylnicotinates synthesis.
R1
O
N
O
O
CO2R2
OAc
O
DABCO (1.5 equiv)
S
R1
OR2
+
2-MeTHF, 70 °C, O2,
36-80 h
R
N
R
1a-j
2a-k
3aa-3jg
Me
OBn
X
OMe
CO2R2
CO2Et
CO2Et
CO2Et
thiophenylꢀ2ꢀarylnicotinonitriles
after 24h when a 4ꢀthiophenyl cyclic sulfamidate imine 1i
was used for this reaction
(3il-3in) were obtained
Ph
N
Ph
N
Ph
N
Ph
N
3aa: R2 = Et; 82%, 48h
3aa : R2 = Me; 80%, 48h
3ad: X = F; 87%, 40h
3ae: X = Cl; 85%, 40h
3af: X = Br; 85%, 40h
3ab: 81%, 48h
3ac: 77%, 72h
.
X
NO2
O2N
Ph
Table 3. Synthesis of 4,6ꢀdiarylnicotonitriles.
CO2Et
CO2Et
CO2Me
CO2Et
Ph
N
Ph
N
Ph
N
Ph
N
3ak: 67%, 40h
NO2
3ag: X = CF3, 86%, 36h
3ah: X = CN, 83%, 36h
3ai: 83%, 36h
3aj: 84%, 36h
X
X
CO2Me
CO2Et
CO2Et
CO2Et
Me
N
N
N
N
3bd: X = F; 86%, 40h
3be: X = Cl;85%, 40h
3bf: X = Br; 83%, 40h
Me
Me
Me
3ba: 84%, 48h
3bg: X =CF ; 85%, 36h
3bj: 84%, 36h
3
3bh: X = CN; 83%, 36h
X
NO2
O2N
CO2Et
CO2Et
CO2Et
CO2Me
N
N
N
N
MeO
MeO
MeO
3cj: 84%, 36h
MeO
3ci: 82%, 36h
3cd: X = F; 85%, 40h
3cg: X = CF3;84%, 36h
X
3ca: 83%, 48h
X
OBn
MeO
CF3
CO2Et
CO2Et
CO2Et
CO2Et
F
OMe
OMe
N
N
N
N
3ea: X = H; 77%, 60h
3eb: X =Me;75%, 60h
3eg: X = CF3; 81%,40h
Cl
F
3dg: 77%, 36h
3fa: X = H; 80%, 60h
3fh: X = CN;82%, 40h
3ec: 74%, 80h
X
X
NO2
CO2Et
CO2Et
CO2Et
CO2Me
Cl
N
N
N
N
S
S
3id: X = F;76%, 48h
3if: X = Br; 72%, 48h
3ia: 70%, 60h
Br
In order to further expand the possible substrate scope, we were
3gj: 82%, 48h
3ha: X = H; 81%, 60h
3hg: X = CF3;85%, 40h
CF3
CF3
inspired to use arylꢀsubstituted MBH acetates of MVK (2t-2u
)
O2N
as chemically challenging acceptors for this domino reaction.
Gratifyingly, by using the cyclic imines (1a-i), all of the
transformations were found reasonably clean and furnished 74ꢀ
CO2Et
CO2Et
CO2Et
N
3ig: 77%, 40h
N
N
S
S
O
3ii: 74%, 40h
3jg: 72%, 40h
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General information:
All the 4ꢀaryl/heteroarylꢀ5Hꢀ1,2,3ꢀoxathiazoleꢀ2,2ꢀdioxides
83% yields of 3ꢀacetylpyridines (3at-3iu) after 40ꢀ48h (Table
4). Usually, they are very difficult to prepare through the
conventional methods.13
16
17
(
1a-j
)
and MoritaꢀBaylisꢀHillman acetates (2a-2l
)
were
synthesized by literature known procedures. All the bases were
purchased from commercial sources (SigmaꢀAldrich). All the
reactions were carried out under O2 atmosphere and monitored
by TLC using Merck 60 F254 pre coated silica gel plates (0.25
mm thickness) and the products were visualized by UV
detection. Flash chromatography was carried out with silica gel
Table 4. Substrate scope of MBH acetates of MVK.
(200ꢀ300 mesh). FTꢀIR spectra were recorded on
a
BrukerTensorꢀ27 spectrometer. H and 13C NMR spectra were
recorded on a Bruker Avance (III) 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
1
=
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 ESIꢀTOFꢀMS.
Representative one-pot procedure for the synthesis of ethyl 4,6-
diphenylnicotinate (3aa):
Finally, to demonstrate the potential utility of prepared
compound, 3al was further converted into a potential PDE10A
inhibitor14 triazolopyridine derivative
reported method15 (Scheme 6).
9 in 81% yield using a
To a stirred solution of compound 1a (39.4 mg, 0.2 mmol) and 2a
(54.6 mg, 0.22 mmol) in 2ꢀMeTHF (1.0 mL) was added DABCO
(33.6 mg, 0.3 mmol) at room temperature. Then the reaction mixture
was heated at 70 °C for 48h under O2 atmosphere (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, dried over Na2SO4. The combined organic phases
were evaporated under reduced pressure to afford the crude product.
Finally it was obtained in a pure form (49.7 mg, 82%) through
column chromatography over silicaꢀgel using
a mixture of
Scheme 3. Synthesis of the triazolopyridine derivative 9
EtOAc/hexane (1:4, v/v) as the eluent. The product was fully
1
characterized by its spectroscopic data (IR, HNMR, 13C NMR and
HRMS).
Conclusions
In the current manuscript, we have established a general,
expedient, metalꢀfree based novel domino reaction of several
aryl/heteroarylꢀsubstituted cyclic sulfamidate imines as suitable
nucleophiles with a broad range of MBH acetates bearing
ester/cyano/acetyl groups in the presence of DABCO as a base
under O2 atmosphere at 70 °C. This unprecedented tactic
All the products (3ab-3jg) in Table 2, 3al-3in in Table 3 and
3at-3iu in Table 4 were synthesized following the above
procedure. All the products were characterized by their
corresponding spectroscopic data (IR, 1H, 13C NMR and
HRMS).
Ethyl 4,6-diphenylnicotinate (3aa):7j White solid; Yield: 82% (49.7
mg); mp 110ꢀ112 °C; Rf = 0.85 (EtOAc:hexane = 1:4); IR (KBr) ν
1700, 1585, 1534, 1493, 1467, 1443, 1363, 1299 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 9.13 (s, 1H), 8.07 (d, J = 6.8 Hz, 2H), 7.72 (s,
1H), 7.44ꢀ7.51 (m, 6H), 7.37ꢀ7.39 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H),
1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1,
159.8, 151.5, 151.4, 139.5, 138.6, 130.1, 129.2, 128.6, 128.5, 128.3,
127.6, 125.1, 122.0, 61.5, 14.0; HRMS (ESI) m/z calcd for
C20H18NO2 [M+H]+: 304.1332, found 304.1362.
delivers
carboxylate/cyano/acetylꢀ4,6ꢀdiarylpyridine derivatives in high
to excellent yields. Moreover, this smart potꢀeconomy
a
series of pharmacologically valuable 3ꢀ
approach eliminates the use of highly expensive and toxic
metalꢀsalts, strong acids, large excess of external oxidants,
multistep etc. In addition, the operational simplicity, broad
substrate generality, compatibility with a variety of functional
groups on the aryl rings and high to excellent yields make this
procedure more powerful alternative to the established
methods. Additional efforts towards the application of this
method to generate therapeutically active pyridine derivatives
are under progress.
Methyl 4,6-diphenylnicotinate (3aa´):7r White solid; Yield: 80%
(46.3 mg); mp 108ꢀ110 °C; Rf = 0.85 (EtOAc:hexane = 1:4); IR
(KBr): ν 1704, 1588, 1535, 1494, 1468, 1432, 1371, 1297, 1228, cmꢀ
1
1; H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.06 (d, J = 6.8 Hz,
2H), 7.72 (s, 1H), 7.45ꢀ7.51 (m, 6H), 7.37ꢀ7.39 (m, 2H), 3.73 (s,
Experimental Section
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3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 160.0, 151.6, 151.5, Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
139.3, 138.5, 130.2, 129.2, 128.8, 128.6, 128.3, 127.6, 124.6, 122.1, CDCl3)δ166.6, 160.1, 151.8, 150..4, 138.4, 138.3, 131.7, 130.3,
52.5; HRMS (ESI) m/z calcd for C19H15NO2Na [M+Na]+: 312.0995, 130.0, 129.2, 127.6, 124.5, 123.0, 121.8, 61.6, 14.1; HRMS (ESI)
found 312.0981.
m/z
calcd for C20H1679BrNO2Na[M+Na]+
: 404.0257, found
404.0202; HRMS (ESI) m/z calcd for C20H1681BrNO2Na[M+Na]+
:406.0237, found 406.0186.
Ethyl 6-phenyl-4-(4-methylphenyl)nicotinate (3ab):7j White solid;
Yield: 81% (51.4 mg); mp 114ꢀ116 °C; Rf = 0.85 (EtOAc:hexane =
1:4); IR (KBr) ν 1696, 1594, 1573, 1534, 1468, 1444, 1373, 1299,
Ethyl
6-phenyl-4-(4-trifluoromethylphenyl)nicotinate(3ag):
1
1231 cmꢀ1; H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.04 (d, J =
White solid; Yield: 86% (63.8 mg); mp 127ꢀ129 °C; Rf = 0.75
(EtOAc:hexane = 1:4); IR (KBr) ν 1699, 1592, 1574, 1537, 1471,
1362, 1328, 1302, 1234 cmꢀ1; H NMR (400 MHz, CDCl3)δ9.22 (s,
1H), 8.06ꢀ8.08 (m, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.68 (s, 1H), 7.48ꢀ
7.53 (m, 5H), 4.19 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3)δ166.2, 160.1, 151.8, 150.4, 143.3, 138.0,
131.3, 131.0, 130.6, 130.5, 130.3, 129.3, 128.8, 127.7, 125.7, 125.5,
125.5, 125.4, 125.4, 124.4, 123.0, 121.8, 61.7, 14.0; HRMS (ESI)
m/z calcd for C21H16F3NO2Na[M+Na]+ 394.1025, found 394.1025.
6.7 Hz, 2H), 7.69 (s, 1H), 7.43ꢀ7.49 (m, 3H), 7.23ꢀ7.28 (m, 4H),
4.19 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H), 1.11 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ167.2, 159.7, 151.4, 151.3, 138.6, 138.6,
136.4, 130.0, 129.3, 129.1, 128.3, 127.5, 125.1, 122.0, 61.5, 21.5,
14.1;HRMS (ESI) m/z calcd for C21H19NO2Na[M+Na]+ : 340.1308,
found 340.1312.
1
Ethyl
4-(4-benzyloxy-3-methoxyphenyl)-6-phenylnicotinate
(3ac): White solid; Yield: 77% (67.7 mg); mp 125ꢀ127 °C; Rf =
0.62 (EtOAc:hexane = 1:4); IR (KBr) ν 1704, 1591, 1533, 1510,
1467, 1414, 1373, 1303, 1240, 1205 cmꢀ1; 1H NMR (400 MHz,
CDCl3)δ9.07 (s, 1H), 8.06 (d, J = 6.7 Hz, 2H), 7.71 (s, 1H), 7.44ꢀ
7.50 (m, 5H), 7.36ꢀ7.40 (m, 2H), 7.31ꢀ7.33 (m, 1H), 6.93ꢀ6.97 (m,
2H), 6.88ꢀ6.90 (m, 1H), 5.21 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.91
(s, 3H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ167.4, 159.6, 151.1, 150.8, 149.6, 148.8, 138.5, 137.1, 132.3(2C),
130.0, 129.1, 128.8, 128.2, 127.5, 125.3, 121.7, 120.9, 113.8, 112.2,
Ethyl 4-(4-cyanophenyl)-6-phenylnicotinate(3ah): Light yellow
solid; Yield: 83%(54.5 mg); mp 130ꢀ132 °C; Rf
= 0.45
(EtOAc:hexane = 1:4); IR (KBr) ν 2225, 1697, 1591, 1572, 1535,
1502, 1468, 1444, 1403, 1374, 1362, 1318, 1300, 1231 cmꢀ1; 1H
NMR (400 MHz, CDCl3)δ 9.15 (s, 1H), 7.98ꢀ8.00 (m, 2H), 7.67 (d,
J = 8.0 Hz, 2H), 7.56 (s, 1H), 7.38ꢀ7.42 (m, 5H), 4.12 (q, J = 7.2 Hz,
2H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6,
160.0, 151.8, 149.6, 144.0, 137.7, 131.9, 130.2, 128.9 (2C), 127.3,
123.6, 121.1, 118.5, 112.1, 61.4, 13.8;HRMS (ESI) m/z calcd for
C21H17N2O2[M+H]+ 329.1285, found 329.1283.
71.2, 61.5, 56.3, 14.1;HRMS (ESI) m/z
C28H25NO4Na[M+Na]+: 462.1676, found 462.1664.
calcd for
Ethyl 4-(4-fluorophenyl)-6-phenylnicotinate(3ad): White solid;
Yield: 87% (55.9 mg); mp 118ꢀ120°C; Rf = 0.84 (EtOAc:hexane = Ethyl 4-(3-nitrophenyl)-6-phenylnicotinate(3ai): Light yellow
1:4); IR (KBr)ν 1697, 1594, 1536, 1507, 1469, 1401, 1370, 1301, solid; Yield: 83%(57.8 mg); mp 135ꢀ137 °C; Rf 0.45
=
1226 cmꢀ1; H NMR (400 MHz, CDCl3)δ 9.14 (s, 1H), 8.05 (d, J = (EtOAc:hexane = 1:4); IR (KBr) ν 1720, 1593, 1579, 1528, 1481,
6.5 Hz, 2H), 7.67 (s, 1H), 7.46ꢀ7.52 (m, 3H), 7.33ꢀ7.36 (m, 2H), 1470, 1443, 1362, 1348, 1286, 1245, 1230 cmꢀ1; 1H NMR (400
7.14 (t, J = 8.7 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 MHz, CDCl3)δ 9.26 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H),
Hz, 3H);13C NMR (100 MHz, CDCl3) δ 166.8, 163.2 (d, JCꢀF= 246 8.07ꢀ8.09 (m, 2H), 7.62ꢀ7.70 (m, 3H), 7.48ꢀ7.53 (m, 3H), 4.22 (q, J
Hz) 160.0, 151.6, 150.5, 138.4, 135.5 (d, JCꢀF= 3.6 Hz), 130.2 ( d, JCꢀ = 6.8 Hz, 2H), 1.16 (t, J = 3H); 13C NMR (100 MHz, CDCl3)δ 165.6,
F= 8.0 Hz), 129.2, 127.6, 124.9, 122.0, 115.6 (d, JCꢀF= 21.8 Hz), 160.2, 151.9, 149.0, 148.0, 140.9, 137.6, 134.2, 130.2, 129.1, 129.0,
61.6, 14.1; HRMS (ESI) m/z calcd For C20H16FNO2Na[M+Na]+ 127.3, 123.6, 123.2, 123.1, 121.5, 61.5, 13.8;HRMS (ESI) m/z calcd
1
:344.1057, found 344.1044.
for C20H17N2O4[M+H]+ 349.1183, found 349.1189.
Ethyl 4-(4-chlorophenyl)-6-phenylnicotinate (3ae):7j White solid;
Yield: 85% (57.3 mg); mp 122ꢀ124 °C; Rf = 0.80 (EtOAc:hexane =
1:4); IR (KBr) ν 1696, 1596, 1573, 1532, 1490, 1468, 1399, 1371,
Methyl 4-(4-nitrophenyl)-6-phenylnicotinate(3aj): Light yellow
solid; Yield: 84% (56.1 mg); mp 136ꢀ138 °C; Rf
= 0.45
(EtOAc:hexane = 1:4); IR (KBr) ν 1721, 1589, 1579, 1538, 1508,
1474, 1445, 1433, 1355, 1348, 1322, 1295, 1247, 1231 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.33 (d, J = 8.8 Hz, 2H),
1
1296, 1230cmꢀ1; H NMR (400 MHz, CDCl3)δ9.15 (s, 1H), 8.06 (d,
J = 6.8 Hz, 2H), 7.66 (s, 1H), 7.46ꢀ4.51 (m, 3H), 7.42ꢀ7.44 (m, 2H),
7.30ꢀ7.32 (m, 2H), 4.21 (q, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H)
8.06ꢀ8.09 (m, 2H), 7.67 (s, 1H), 7.49ꢀ7.54 (m, 5H), 3.77 (s, 3H); 13
C
;
13C NMR (100 MHz, CDCl3) δ166.7, 160.1, 151.7, 150.4, 138.4,
NMR (100 MHz, CDCl3)δ 165.9, 160.2, 151.8, 149.5, 147.7, 145.8,
137.6, 130.3, 129.1, 129.0, 127.3, 123.4, 123.1, 121.3, 52.3; HRMS
(ESI) m/z calcd for C19H15N2O4[M+H]+ 335.1026, found 335.1026.
Ethyl 4-(E)-styryl-6-phenylnicotinate (3ak): White solid; Yield:
67% (44.1 mg); mp 74ꢀ76 °C; Rf = 0.84 (EtOAc:hexane = 1:9); IR
(KBr): 1715, 1628, 1583, 1531, 1446, 1371, 1274, 1217, 1173, 1093,
1021, 961 ν cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.04ꢀ
8.09 (m, 3H), 7.96 (s, 1H), 7.55ꢀ7.58 (m, 2H), 7.43ꢀ7.49 (m, 2H),
7.27ꢀ7.38 (m, 3H), 7.21 (s, 1H), 7.11ꢀ7.15 (m, 1H), 4.40 (q, J = 6.8
Hz, 2H), 1.40 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
137.9, 134.9, 130.3, 129.8, 129.2, 128.8, 127.6, 124.6, 121.8, 61.6,
14.1; HRMS (ESI) m/z
360.0762, found 360.0791.
calcd for C20H16ClNO2Na[M+Na]+:
Ethyl 4-(4-bromophenyl)-6-phenylnicotinate (3af): Light yellow
solid; Yield: 85%(64.8 mg); mp130ꢀ132°C; Rf 0.85
=
(EtOAc:hexane = 1:4);IR (KBr) ν 1697, 1597, 1573, 1531, 1489,
1469, 1446, 1394, 1376, 1361, 1298, 1233 cmꢀ1; 1H NMR (400
MHz, CDCl3)δ9.15 (s, 1H), 8.04ꢀ8.06 (m, 2H), 7.65 (s, 1H), 7.56ꢀ
7.60 (m, 2H), 7.45ꢀ7.51 (m, 3H), 7.22ꢀ7.25 (m, 2H), 4.20 (q, J = 7.2
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Hz, 2H), 2.42 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz,
CDCl3)δ 166.3, 160.2, 151.9, 150.2, 143.5, 140.7, 135.4, 131.2,
130.9, 130.5, 130.2, 130.0, 128.8, 127.5, 125.7, 125.5, 125.4, 125.4,
125.3, 124.0, 123.0, 121.4, 61.6, 21.6, 14.0; HRMS (ESI) m/z calcd
for C22H18F3NO2Na[M+Na]+ 408.1182, found 408.1183.
166.2, 160.0, 152.4, 147.4, 138.5, 136.5, 134.8, 129.8, 128.9, 128.8
(2 C), 127.3 (2 C), 125.3, 122.1, 117.0, 61.3, 14.3; HRMS (ESI) m/z
calcd for C22H19NO2[M+H]+ : 330.1489, found 330.1502.
Ethyl 4-phenyl-6-(4-methylphenyl)nicotinate (3ba): White solid;
Yield: 84% (55.2 mg); mp 114ꢀ116 °C; Rf = 0.85 (EtOAc:hexane =
1:4); IR (KBr) ν 1698, 1588, 1532, 1469, 1443, 1363, 1310, 1232 Ethyl 4-(4-cyanophenyl)-6-(4-methylphenyl)nicotinate (3bh):
1
cmꢀ1; H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.97 (d, J = 8.2
White solid; Yield: 83% (56.8 mg); mp 134ꢀ136 °C; Rf = 0.45
Hz, 2H), 7.69 (s, 1H), 7.44ꢀ7.45 (m, 3H), 7.36ꢀ7.38 (m, 2H), 7.29 (d,
J = 8.0 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.07 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ167.1, 159.8, 151.4,
151.4, 140.3, 139.6, 135.7, 129.9, 128.6, 128.5, 128.3, 127.5, 124.7,
(EtOAc:hexane = 1:4); IR (KBr) ν 2227, 1696, 1592, 1532, 1503,
1469, 1363, 1322, 1296, 1232 cmꢀ1;1H NMR (400 MHz,
CDCl3)δ9.13 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz,
2H), 7.53 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H),
4.11 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.06 (t, J = 7.2Hz, 3H; 13C
NMR (100 MHz, CDCl3)δ 165.7, 160.0, 151.8, 149.5, 144.2, 140.5,
134.9, 131.9, 129.7, 128.9, 127.2, 123.2, 120.8, 118.5, 112.1, 61.3,
21.3, 13.8; HRMS (ESI) m/z calcd for C22H19N2O2[M+H]+
343.1441, found 343.1449.
121.6, 61.4, 21.6, 14.0; HRMS (ESI) m/z
C21H20NO2[M+H]+318.1489, found 318.1491.
calcd for
Ethyl
4-(4-fluorophenyl)-6-(4-methylphenyl)nicotinate
(3bd):White solid; Yield: 86% (57.7 mg); mp 125ꢀ127 °C; Rf =0.84
(EtOAc:hexane = 1:4); IR (KBr) ν 1696, 1594, 1533, 1507, 1469,
1448, 1369, 1298, 1227 cmꢀ1; 1H NMR (400 MHz, CDCl3)δ 9.12 (s,
1H), 7.96 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.29ꢀ7.36 (m, 4H), 7.14
(t, J = 8.5 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.13 (t, J
Methyl 4-(4-nitrophenyl)-6-(4-methylphenyl)nicotinate (3bj):
White solid; Yield: 84% (58.5 mg); mp 140ꢀ142 °C; Rf = 0.45
(EtOAc:hexane = 1:4); IR (KBr) ν 1712, 1587, 1538, 1513, 1432,
= 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3)δ 166.9, 163.2(d, JCꢀF
=
1
1346, 1318, 1291, 1228 cmꢀ1; H NMR (400 MHz, CDCl3)δ 9.23
246.0 Hz),160.0, 151.6, 150.4, 140.5, 135.6 (d, JCꢀF= 3.6 Hz), 130.2,
129.9, 127.5, 124.5, 121.6, 115.7, 115.4, 61.5, 21.6, 14.1; HRMS
(ESI) m/z calcd for C21H19FNO2[M+H]+ 336.1394, found 336.1386.
(s,1H), 8.32 (d, J = 8.0, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H),
7.52 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.76 (s, 3H), 2.42
(s, 3H);13C NMR (100 MHz, CDCl3)δ 166.0, 160.2, 151.9, 149.5,
147.7, 146.0, 140.7, 134.8, 129.7, 129.1, 127.2, 123.4, 122.7, 120.9,
52.3, 21.4; HRMS (ESI) m/z calcd for C20H17N2O4[M+H]+
349.1183, found 349.1184.
Ethyl 4-(4-chlorophenyl)-6-(4-methylphenyl)nicotinate (3be):
White solid; Yield: 85% (59.7 mg); mp 127ꢀ129 °C; Rf = 0.80
(EtOAc:hexane = 1:4); IR (KBr) ν 1694, 1593, 1570, 1530, 1491,
1468, 1397, 1362, 1293, 1231, 1183 cmꢀ1; 1H NMR (400 MHz,
CDCl3)δ9.14 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H), 7.41ꢀ
7.43 (m, 2H), 7.29ꢀ7.31 (m, 4H), 4.20 (q, J = 7.0 Hz, 2H), 2.41 (s,
3H), 1.14 (t, J = 7.0Hz, 3H); 13C NMR (100 MHz, CDCl3) δ166.7,
160.0, 151.7, 150.3, 140.5, 138.1, 135.5, 134.8, 129.9, 129.8, 128.7,
127.5, 124.3, 121.5, 61.6, 21.6, 14.1;HRMS (ESI) m/z calcd for
C21H18ClNO2Na[M+Na]+ 374.0918, found 374.0908.
Ethyl 6-(4-methoxyphenyl)-4-phenylnicotinate (3ca):7j White
solid; Yield: 83% (57.3 mg); mp 120ꢀ122 °C; Rf
= 0.80
(EtOAc:hexane = 1:4); IR (KBr) ν 1713, 1591, 1530, 1514, 1472,
1443, 1420, 1363, 1320, 1300, 1252, 1231 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 9.10 (s, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.64 (s, 1H),
7.43ꢀ7.44 (m, 3H), 7.36ꢀ7.37 (m, 2H), 7.00 (d, 8.5 Hz, 2H), 4.16 (q,
J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ167.1, 161.5, 159.4, 151.5, 151.4, 139.7, 131.1,
129.0, 128.5, 128.5, 128.3, 124.2, 121.1, 114.5, 61.4, 55.7,
14.0;HRMS (ESI) m/z calcd for C21H20NO3[M+H]+ 334.1438,
found 334.1452.
Ethyl 4-(4-bromophenyl)-6-(4-methylphenyl)nicotinate (3bf):
White solid; Yield: 83% (65.7 mg); mp 135ꢀ137 °C; Rf = 0.84
(EtOAc:hexane = 1:4); IR (KBr) ν 1694, 1594, 1570, 1530, 1488,
1467, 1393, 1361, 1294, 1232cmꢀ1; 1H NMR (400 MHz,
CDCl3)δ9.11 (s, 1H), 7.93 (d, J = 6.7 Hz, 2H), 7.60 (s, 1H), 7.55 (d,
J = 6.7 Hz, 2H), 7.26 (d, J = 7.2 Hz, 2H), 7.20ꢀ7.22 (m, 2H), 4.17
(q, J = 7.0 Hz, 2H), 2.38 (s, 3H), 1.12 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ166.6, 160.0, 151.7, 150.3, 140.5, 138.5, 135.5,
131.6, 130.0, 129.9, 127.5, 124.2, 122.9, 121.4, 61.6, 21.6,
14.1;HRMS (ESI) m/z calcd for C21H1979BrNO2[M+H]+ 396.0594,
found 396.0589; HRMS (ESI) m/z calcd for C21H1981BrNO2[M+H]+
398.0574, found 398.0574.
Ethyl
4-(4-fluorophenyl)-6-(4-methoxyphenyl)nicotinate(3cd):
White solid; Yield: 85% (59.7 mg); mp 131ꢀ133 °C; Rf = 0.80
(EtOAc:hexane = 1:4); IR (KBr) ν 1693, 1601, 1533, 1509, 1469,
1
1366, 1299, 1251, 1224 cmꢀ1; H NMR (400 MHz, CDCl3)δ9.10 (s,
1H), 8.03 (d, J = 8.8 Hz, 2H), 7.59 (s, 1H), 7.32ꢀ7.35 (m, 2H), 7.13
(t, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 4.18 (q, J = 7.2 Hz,
2H), 3.86 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.8, 163.1(d, JCꢀF= 246 Hz), 161.6, 159.6, 151.7, 150.4,
135.7 (d, JCꢀF= 3.6 Hz), 130.9, 130.2 (d, JCꢀF= 8.0 Hz), 129.0, 124.0,
121.1, 115.6 (d, JCꢀF= 21.9 Hz), 114.6, 61.5, 55.7, 14.1; HRMS (ESI)
m/z calcd for C21H18FNO3Na[M+Na]+ 374.1163, found 374.1161.
Ethyl 6-(4-methylphenyl)-4-(4-trifluoromethylphenyl)nicotinate
(3bg):White solid; Yield: 85%(65.5 mg); mp134ꢀ136 °C; Rf = 0.75
(EtOAc:hexane = 1:4); IR (KBr) ν 1698, 1592, 1571, 1536, 1470,
Ethyl
6-(4-methoxyphenyl)-4-(4-
1
1363, 1327, 1296, 1233 cmꢀ1; H NMR (400 MHz, CDCl3)δ9.20 (s,
trifluoromethylphenyl)nicotinate (3cg): White solid; Yield: 84%
(67.4 mg); mp140ꢀ142 °C; Rf = 0.67 (EtOAc:hexane = 1:4); IR
(KBr) ν 1700, 1606, 1595, 1574, 1536, 1521, 1470, 1363, 1325,
1H), 7.97 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H),
7.48 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.18 (q, J = 7.2
6 | J. Name., 2012, 00, 1-3
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1
1300, 1251, 1232 cmꢀ1; H NMR (400 MHz, CDCl3)δ 9.17 (s, 1H), 14.0;HRMS (ESI) m/z calcd for C20H17FNO2[M+H]+ 322.1238,
8.04 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.47 found 322.1224.
(d, J = 7.7 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.17 (q, J = 7.0 Hz,
2H), 3.86 (s, 3H), 1.09 (t, J = 7.0 Hz, 3H);13C NMR (100 MHz,
Ethyl
6-(4-fluorophenyl)-4-(4-methylphenyl)nicotinate
CDCl3) δ166.3, 161.7, 159.8, 151.9, 150.2, 143.5, 131.1, 130.8,
130.7, 130.4, 130.1, 129.0, 128.8, 128.4, 125.7, 125.4, 125.4, 125.3,
125.3, 123.4, 123.0, 120.8, 120.3, 114.6, 61.5, 55.6, 14.0; HRMS
(ESI) m/z calcd for C22H18F3NO3Na[M+Na]+ 424.1131, found
424.1127.
(3eb):White solid; Yield: 75% (50.3 mg); mp 126ꢀ128 °C; Rf =
0.83(EtOAc:hexane = 1:4); IR (KBr) ν 1692, 1598, 1535, 1510,
1468, 1363, 1323, 1300, 1231 cmꢀ1; 1H NMR (400 MHz,
CDCl3)δ9.07 (s, 1H), 8.03ꢀ8.06 (m, 2H), 7.64 (s, 1H), 7.26 (s, 4H),
7.15 (t, J = 8.5 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H),
1.12(t, J = 7.0Hz, 3H); 13C NMR (100 MHz, CDCl3) δ167.1,
Ethyl 6-(4-methoxyphenyl)-4-(3-nitrophenyl)nicotinate (3ci): 164.3(d, JCꢀF= 248 Hz), 158.6, 151.5, 151.4, 138.7, 136.3, 134.8 (d,
White solid; Yield: 82% (65.6 mg); mp 142ꢀ144 °C; Rf = 0.40 JCꢀF= 3.6.0 Hz), 129.5 (d, JCꢀF= 8.0 Hz), 129.3, 128.2, 125.0, 121.6,
(EtOAc:hexane = 1:4); IR (KBr) ν 1704, 1586, 1535, 1466, 1442, 116.2(d, JCꢀF= 21.0 Hz), 61.5, 21.5, 14.1;HRMS (ESI) m/z calcd for
1347, 1297, 1255, 1223 cmꢀ1;1H NMR (400 MHz, CDCl3) δ9.22 (s, C21H18FNO2Na[M+Na]+358.1214, found 358.1207.
1H), 8.30 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 8.05 (d, J = 8.8 Hz, 2H),
7.61ꢀ7.69 (m, 3H), 7.01 (d, J = 8.8 Hz, 2H), 4.20 (q, J = 6.8Hz, 2H),
3.87 (s, 3H), 1.51 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)δ
165.6, 161.5, 159.8, 151.9, 148.9, 147.9, 141.1, 134.3, 130.1, 129.0,
128.8, 123.2, 123.0, 122.7, 120.5, 114.3, 61.3, 55.4, 13.8;HRMS
(ESI) m/z calcd for C21H18N2O5Na[M+Na]+ 401.1108, found
401.1121.
Ethyl 6-(4-fluorophenyl)-4-(4-trifluoromethylphenyl)nicotinate
(3eg): White solid; Yield: 81% (66.6 mg); mp 145ꢀ147 °C; Rf = 0.72
(EtOAc:hexane = 1:4); IR (KBr)ν 1694, 1595, 1534, 1514, 1469,
1407, 1365, 1325, 1299, 1233 cmꢀ1; 1H NMR (400 MHz,
CDCl3)δ9.19 (s, 1H), 8.05ꢀ8.09 (m, 2H), 7.72 (d, J = 8.0 Hz, 2H),
7.62 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.18
(q, J = 7.2 Hz, 2H), 1.09 (t, 3H);13C NMR (100 MHz, CDCl3)
Methyl 6-(4-methoxyphenyl)-4-(4-nitrophenyl)nicotinate (3cj): δ166.2, 164.5 (d, JCꢀF= 249 Hz), 159.1, 152.0, 150.4, 143.2, 134.4 (d,
Light yellow solid; Yield: 84% (61.2 mg); mp 144ꢀ146 °C; Rf = 0.35 JCꢀF= 3.6 Hz), 131.4, 131.0, 130.7, 130.4, 129.6 (d, JCꢀF= 8.0 Hz),
(EtOAc:hexane = 1:4); IR (KBr) ν 1724, 1590, 1542, 1514, 1476, 128.8, 125.7, 125.5, 125.5, 125.5, 125.4, 124.3, 123.0, 121.4, 116.4
1435, 1353, 1292, 1242 cmꢀ1;1H NMR (400 MHz, CDCl3)δ 9.21 (s, (d, JCꢀF= 21.8 Hz), 61.7, 14.0; HRMS (ESI) m/z calcd for
1H), 8.31 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.59 (s, 1H), C21H15F4NO2Na[M+Na]+ 412.0931, found 412.0935.
7.51 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.76
(s, 3H); 13C NMR (100 MHz, CDCl3)δ 165.9, 161.5, 159.8, 151.8,
Ethyl
4-(4-benzyloxy-3-methoxyphenyl)-6-(4-
149.4, 147.6, 146.1, 130.0, 129.0, 128.8, 123.3, 122.2, 120.3, 114.3,
55.4, 52.2; HRMS (ESI) m/z
365.1132, found 365.1137.
fluorophenyl)nicotinate (3ec): White solid; Yield: 74% ( 67.7mg);
mp 135ꢀ137 °C; Rf = 0.60 (EtOAc:hexane = 1:4); IR (KBr) ν 1728,
1601, 1584, 1537, 1509, 1471, 1454, 1411, 1366, 1318, 1261, 1231,
1205, cmꢀ1; 1H NMR (400 MHz, CDCl3)δ9.03 (s, 1H), 8.03ꢀ8.07 (m,
calcd for C20H17N2O5[M+H]+
Ethyl
6-(2,5-dimethoxyphenyl)-4-(4-trifluoromethyl 2H), 7.65 (s, 1H), 7.45ꢀ7.47 (m, 2H), 7.38 (t, J = 7.0 Hz, 2H), 7.31ꢀ
phenyl)nicotinate (3dg): White solid; Yield: 77% (66.4 mg); 7.33 (m, 1H), 7.16 (t, J = 8.2 Hz, 2H), 6.86ꢀ6.97 (m, 3H), 5.2 (s,
mp146ꢀ148 °C; Rf =0.63(EtOAc:hexane = 1:4); IR (KBr) ν 1720, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 1.09 (t, J =7.2 Hz, 3H);
1587, 1541, 1502, 1466, 1424, 1370, 1326, 1285, 1229, 1205 cmꢀ 13C NMR (100 MHz, CDCl3) δ167.4, 164.2(d, JCꢀF = 248.0 Hz),
1;1H NMR (400 MHz, CDCl3)δ 9.19 (s, 1H), 7.89 (s, 1H), 7.70 (d, J 158.6, 151.2, 150.9, 149.7, 148.8, 137.1, 134.8 (d, JCꢀF= 3.6 Hz),
= 8.0 Hz, 2H), 7.47ꢀ7.51 (m, 3H), 6.93ꢀ6.99 (m, 2H), 4.18 (q, J = 132.3, 129.5 (d, JCꢀF= 8.7 Hz), 128.9, 128.2, 127.5, 125.3, 121.4,
7.2 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H);13C 120.9, 116.2 (d, JCꢀF= 21.1 Hz), 113.9, 112.2, 71.2, 61.5, 56.4, 14.1;
NMR (100 MHz, CDCl3)δ165.5, 157.7, 153.3, 150.9, 150.3, 148.0, HRMS (ESI) m/z calcd for C28H24FNO4Na[M+Na]+: 480.1582,
142.5, 130.1, 129.7, 129.4, 129.1, 129.0, 127.9, 127.4, 125.3, 124.7, found 480.1564.
124.4, 124.4, 124.4, 124.3, 123.0, 122.0, 116.2, 115.1, 112.4, 60.6,
55.6, 55.2, 13.0; HRMS (ESI) m/z calcd for C23H21F3NO4[M+H]+
432.1417, found 432.1401.
Ethyl 6-(4-chlorophenyl)-4-phenylnicotinate (3fa):7jWhite solid;
Yield: 80% (53.9 mg); mp 124ꢀ126 °C; Rf = 0.85 (EtOAc:hexane =
1:4); IR (KBr) ν 1702, 1590, 15321, 1494, 1467, 1363, 1308, 1290,
1
Ethyl 6-(4-fluorophenyl)-4-phenylnicotinate(3ea):White solid; 1232, cmꢀ1; HNMR (400 MHz, CDCl3)δ9.11 (s, 1H), 8.01 (d, J =
Yield: 77% (49.5 mg); mp 119ꢀ121 °C; Rf = 0.83 (EtOAc:hexane = 8.5 Hz, 2H), 7.68 (s, 1H), 7.44ꢀ7.47 (m, 5H), 7.35ꢀ7.37 (m, 2H),
1:4); IR (KBr) ν 1697, 1584, 1534, 1514, 1468, 1366, 1297, 1230 4.17 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.05ꢀ8.08 (m, 2H), MHz, CDCl3) δ167.0, 158.5, 151.6, 151.5, 139.3, 137.0, 136.4,
7.66 (s, 1H), 7.44ꢀ7.45 (m, 3H), 7.36ꢀ7.37 (m, 2H), 7.17 (t, J = 8.8 129.4, 128.9, 128.8, 128.6, 128.3, 125.3, 121.7, 61.6, 14.0;HRMS
Hz, 2H), 4.17 (q, J = 7.0 Hz, 2H), 1.07 (t, J = 7.0 Hz, 3H); 13C (ESI) m/z calcd for C20H16ClNO2Na[M+Na]+ 360.0762, found
NMR (100 MHz, CDCl3) δ 167.04, 164.3(d, JCꢀF= 248 Hz), 158.7, 360.0785.
151.6, 151.5, 139.4, 134.7 (d, JCꢀF= 3.6 Hz), 129.5 (d, JCꢀF= 8.7 Hz
128.7, 128.6, 128.3, 125.0, 121.6, 116.2 (d, JCꢀF= 21.0 Hz), 61.5,
Ethyl
6-(4-chlorophenyl)-4-(4-cyanophenyl)nicotinate(3fh):
White solid; Yield: 82% (59.4 mg); mp 138ꢀ140 °C; Rf = 0.44
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(EtOAc:hexane = 1:4);IR (KBr) ν 2224, 1717, 1589, 1536, 1501, Ethyl 4-(4-fluorophenyl)-6-(thiophen-2-yl)nicotinate (3id):White
1
1470, 1404, 1363, 1281, 1225, cmꢀ1; H NMR (400 MHz, CDCl3)δ solid; Yield: 76% (49.7 mg); mp 1120ꢀ122 °C; Rf
= 0.83
9.21 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.61 (EtOAc:hexane = 1:4); IR (KBr) ν 1707, 1587, 1527, 1508, 1471,
(s, 1H), 7.45ꢀ7.48 (m, 4H), 4.20 (q, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 1374, 1299, 1226, cmꢀ1; 1H NMR (400 MHz, CDCl3)δ 9.02 (s,
Hz, 3H); 13C NMR (100 MHz, CDCl3)δ 165.5, 158.7, 151.8, 149.7, 1H),7.66 (d, J = 3.4 Hz, 1H), 7.55 (s, 1H), 7.47 (d, J = 4.7 Hz, 1H),
143.9, 136.5, 136.1, 131.9, 129.2, 128.9, 128.6, 123.8, 120.9, 118.4, 7.31ꢀ7.34 (m, 2H), 7.12ꢀ7.16 (m, 3H), 4.17 (q, J = 7.2 Hz, 2H), 1.12
112.3, 61.5, 13.8;HRMS (ESI) m/z calcd For C21H16ClNO2[M+H]+ (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ166.5, 163.2 (d,
363.0895, found 363.0916.
JCꢀF= 247 Hz),154.9, 151.8, 150.6, 143.8, 135.3 (d, JCꢀF= 2.9 Hz),
130.1(d, JCꢀF= 8.0 Hz), 129.6, 128.6, 126.5, 124.3, 120.1, 115.6 (d,
JCꢀF
=
21.8 Hz) 61.5, 14.1; HRMS (ESI) m/z
calcd for
Methyl
6-(2-chlorophenyl)-4-(4-nitrophenyl)nicotinate(3gj):
C18H14FNO2S[M+Na]+ 350.0621, found 350.0628.
White solid; Yield: 82% (60.4 mg); mp 150ꢀ152 °C; Rf = 0.45
(EtOAc:hexane = 1:4); IR (KBr) ν 1714, 1584, 1539, 1508, 1438,
1427, 1354, 1317, 1293, 1246, 1230 cmꢀ1; 1H NMR (400 MHz, Ethyl 4-(4-bromophenyl)-6-(thiophen-2-yl)nicotinate(3if):White
CDCl3)δ 9.26 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H), 7.68ꢀ7.70 (m, 2H), solid; Yield: 72% (55.7 mg); mp127ꢀ129 °C; Rf
= 0.84
7.49ꢀ7.55 (m, 3H), 7.39ꢀ7.51 (m, 2H), 3.79 (s, 3H); 13C NMR (100 (EtOAc:hexane = 1:4); IR (KBr) ν 1693, 1588, 1524, 1487, 1467,
MHz, CDCl3)δ 165.9, 159.7, 151.5, 148.3, 147.8, 145.3, 137.6, 1425, 1395, 1371, 1303, 1235, 1207, cmꢀ1; 1H NMR (400 MHz,
132.1, 131.6, 130.5, 130.4, 129.2, 127.3, 125.9, 123.7, 123.5, 52.5; CDCl3)δ9.04 (s, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.58 (d, J = 8.2 Hz,
HRMS (ESI) m/z calcd for C19H14ClN2O4[M+H]+ : 369.0637, found 2H), 7.54 (s, 1H), 7.48 (d, J = 4.5 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H),
369.0640.
7.13ꢀ7.15 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3)δ166.3, 155.1, 152.0, 150.5, 143.8,
138.3, 131.7, 130.0, 129.7, 128.7, 126.6, 124.1, 123.1, 119.9, 61.6,
14.1; HRMS (ESI) m/z calcd for C18H1479BrNO2SNa[M+Na]+
Ethyl 6-(4-bromophenyl)-4-phenylnicotinate (3ha):White solid;
Yield: 81% (61.7mg); mp 134ꢀ136 °C; Rf= 0.85 (EtOAc:hexane =
1:4); IR (KBr) ν 1702, 1589, 1532, 1492, 1466, 1443, 1367, 1307,
1232 cmꢀ1; H NMR (400 MHz, CDCl3)δ9.10 (s, 1H), 7.95 (d, J =
409.9821, found 409.9821.HRMS (ESI) m/z
C18H1481BrNO2SNa[M+Na]+ 411.9801, found 411.9800.
calcdfor
1
8.2 Hz, 2H), 7.68 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.44ꢀ7.45 (m,
3H), 7.35ꢀ7.37 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, Ethyl
6-(thiophen-2-yl)-4-(4-trifluoromethylphenyl)nicotinate
3H); 13C NMR (100 MHz, CDCl3) δ167.0, 158.6, 151.6, 151.5, (3ig):White solid; Yield: 77%(58.1 mg); mp 130ꢀ132°C; Rf = 0.72
139.3, 137.4, 132.3, 129.1, 128.8, 128.6, 128.3, 125.4, 124.8, 121.7, (EtOAc:hexane = 1:4); IR (KBr) ν 1707, 1588, 1530, 1473, 1366,
61.6, 14.0;HRMS (ESI) m/z calcd for C20H1679BrNO2Na[M+Na]+ 1330, 1231 cmꢀ1; 1H NMR (400 MHz, CDCl3)δ 9.10 (s, 1H), 7.71 (d,
404.0257, found 404.0246.HRMS (ESI) m/z
C20H1681BrNO2Na[M+Na]+ 406.0237, found 406.0234.
calcd for J = 8.2 Hz, 2H), 7.67 (d, J = 3 Hz, 1H), 7.55 (s, 1H), 7.45ꢀ7.50 (m,
3H), 7.14 (t, J = 4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.2
Hz, 3H);13C NMR (100 MHz, CDCl3)δ166.0, 155.2, 152.1, 150.4,
143.7, 143.1, 131.3, 130.9, 130.6, 130.3, 129.9, 128.7, 128.4, 126.7,
125.7, 125.5, 125.4, 125.4, 125.4, 123.8, 123.0, 119.9, 61.6, 14.0;
HRMS (ESI) m/z calcd for C19H14F3NO2SNa[M+Na]+ 400.0590,
found 400.0588.
Ethyl 6-(4-bromophenyl)-4-(4-trifluoromethylphenyl)nicotinate
(3hg): White solid; Yield: 85% (76.4 mg); mp 150ꢀ152 °C; Rf = 0.74
(EtOAc:hexane = 1:4); IR (KBr) ν 1700, 1590, 1539, 1471, 1367,
1
1327, 1299, 1228 cmꢀ1; H NMR (400 MHz, CDCl3)δ9.19 (s, 1H),
7.95 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.62ꢀ7.64 (m,
3H), 7.47 (d, J = 8.0 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.09 (t, J = Ethyl 4-(3-nitrophenyl)-6-(thiophen-2-yl)nicotinate(3ii): White
7.2 Hz, 3H);13C NMR (100 MHz, CDCl3)δ166.2, 159.0, 152.0, solid; Yield: 74% (52.4mg); mp 140ꢀ142 °C; Rf
0.40
=
150.5, 143.1, 137.1, 132.4, 131.0, 130.7, 129.1, 128.8, 125.6, 125.5, (EtOAc:hexane = 1:4); IR (KBr) ν 1700, 1588, 1530, 1471, 1428,
125.5, 125.4, 125.1, 124.7, 123.0, 121.5, 61.7, 14.0; HRMS (ESI) 1347, 1304, 1240, 1211 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 9.15 (s,
m/z
472.0111.HRMS (ESI) m/z calcd for C21H1581BrF3NO2Na[M+Na]+ (s, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.14ꢀ7.16 (m, 1H), 4.20 (q, J = 7.2
calcd for C21H1579BrF3NO2Na[M+Na]+ 472.0130, found 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.24 (s, 1H), 7.61ꢀ7.70 (m, 3H), 7.56
474.0111, found 474.0110.
Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)δ
165.3, 155.2, 152.1, 149.1, 148.0, 143.2, 140.7, 134.2, 129.8, 129.1,
128.5, 126.7, 123.1(2C), 123.0, 119.6, 61.4, 13.8;HRMS (ESI) m/z
calcd For C18H15N2O4S[M+H]+ 355.0747, found 355.0768.
Ethyl 4-phenyl-6-(thiophen-2-yl)nicotinate (3ia):White solid;
Yield: 70% (43.3 mg); mp 110ꢀ112 °C; Rf = 0.82 (EtOAc:hexane =
1:4); IR (KBr) ν 1693, 1585, 1525, 1468, 1378, 1364, 1303, 1236,
1
1207, cmꢀ1; H NMR (400 MHz, CDCl3)δ9.02 (s, 1H), 7.66 (d, J = Ethyl
6-(furan-2-yl)-4-(4-(trifluoromethylphenyl)nicotinate
3.5 Hz, 1H), 7.60 (s, 1H), 7.44ꢀ7.47 (m, 4H), 7.34ꢀ7.36 (m, 2H), (3jg): White solid; Yield: 72% (51.9mg); mp117ꢀ119°C; Rf = 0.70
7.13 (t, J = 4.0 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.2 (EtOAc:hexane = 1:4); IR (KBr) ν 1719, 1603, 1572, 1539, 1490,
1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ166.7, 154.8, 151.6, 151.5, 1469, 1332, 1281, 1236 cmꢀ1; H NMR (400 MHz, CDCl3)δ9.11 (s,
144.0, 139.3, 129.4, 128.7, 128.6, 128.5, 128.2, 126.4, 124.6, 120.1, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.62 (s, 1H), 7.57 (s, 1H), 7.46 (d, J =
61.4, 14.0;HRMS (ESI) m/z calcd for C18H15NO2SNa[M+Na]+ 8.0Hz, 2H), 7.23 (d, J = 3.2 Hz, 1H), 6.58ꢀ6.59 (m, 1H), 4.17 (q, J =
332.0716, found 332.0726.
7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz,
CDCl3)δ166.1, 152.9, 152.1, 151.7, 150.4, 144.9, 143.2, 131.3,
8 | J. Name., 2012, 00, 1-3
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130.9, 130.6, 130.3, 128.7, 128.4, 125.7, 125.5, 125.4, 125.4, 125.4, CDCl3) δ 161.0, 154.3, 152.0, 137.6, 136.9, 134.6, 131.0, 130.0,
123.8, 123.0, 119.6, 112.9, 111.7, 61.6, 14.0; HRMS (ESI) m/z 129.8, 129.4, 127.7, 120.3, 117.2, 106.6 ; HRMS (ESI) m/z calcd
calcd for C19H15F3NO3[M+H]+ 362.0999, found 362.0994.
for C18H11ClN2Na [M+Na]+ 313.0503, found 313.0507.
2b
4,6-Diphenylnicotinonitrile(3al): White solid; Yield: 88% (45.1 4-(4-Bromophenyl)-6-phenylnicotinonitrile (3ar):White solid;
mg).
Yield: 87% (58.1 mg); mp141ꢀ143 °C; Rf = 0.77 (EtOAc:hexane =
1:4); IR (KBr)ν 2222, 1588, 1531, 1489, 1469, 1441, 1366, 1282,
1242 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ9.00 (s, 1H), 8.07ꢀ8.08 (m,
2H), 7.84 (s, 1H), 7.70 (d, J = 8.5Hz, 2H), 7.52ꢀ7.55 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ161.0, 154.3, 152.1, 137.6, 135.0, 132.8,
131.0, 130.2, 129.4, 127.7, 125.2, 120.3, 117.2, 106.6; HRMS (ESI)
m/z calcd for C18H1179BrN2Na [M+Na]+ 356.9998, found 356.9997.
HRMS (ESI) m/z calcd for C18H1181BrN2Na [M+Na]+ 358.9878,
found 358.9982.
4-(4-Methoxyphenyl)-6-phenylnicotinonitrile (3am):White solid;
Yield: 86% (49.2 mg); mp 118ꢀ120°C, Rf = 0.67 (EtOAc:hexane =
1:4); IR (KBr) ν 2217, 1608, 1581, 1510, 1467, 1373, 1298, 1251
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ8.96 (s, 1H), 8.07 (d, J = 7.5 Hz,
2H), 7.84 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.50ꢀ7.52 (m, 3H), 7.08
(d, J = 8.2 Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ161.6, 160.7, 154.4, 152.9, 137.9, 130.8, 130.2, 129.3, 128.4, 127.7,
120.3, 117.8, 115.0, 106.5, 55.8; HRMS (ESI) m/z calcd for
C19H14N2ONa[M+Na]+ 309.0998, found 309.0999.
6-Phenyl-4-(4-trifluoromethylphenyl)nicotinonitrile (3as): White
solid; Yield: 90% (58.3 mg); mp 138ꢀ140°C; Rf
= 0.73
(EtOAc:hexane = 1:4); IR (KBr) ν 2226, 1586, 1537, 1474, 1443,
1369, 1324cmꢀ1;1H NMR (400 MHz, CDCl3) δ9.04 (s, 1H), 8.08ꢀ
8.10 (m, 2H), 7.87 (s, 1H), 7.77ꢀ7.86 (m, 4H), 7.53ꢀ7.54 (m, 3H);
13C NMR (100 MHz, CDCl3) δ161.1, 154.3, 151.8, 139.7, 137.5,
133.0, 132.6, 132.3, 132.0, 131.2, 129.5, 129.2, 127.8, 126.6, 126.5,
126.5, 126.5, 125.4, 122.7, 120.5, 116.9, 106.8; HRMS (ESI) m/z
calcdfor C19H11F3N2Na [M+Na]+ 347.0767, found 347.0779.
4-(2,5-Dimethoxyphenyl)-6-phenylnicotinonitrile (3an): White
solid; Yield: 85% (53.7 mg); mp 129ꢀ131°C; Rf
= 0.57
(EtOAc:hexane = 1:4); IR (KBr) ν 2223, 1587, 1532, 1502, 1475,
1450, 1409, 1372, 1311, 1264, 1226, cmꢀ1; 1H NMR (400 MHz,
CDCl3) δ8.96 (s, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.83 (s, 1H), 7.49ꢀ
7.51 (m, 3H), 6.98ꢀ7.03 (m, 2H), 6.89 (s, 1H), 3.83 (s, 3H), 3.82 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 154.0, 153.2, 150.8,
150.7, 138.0, 130.6, 129.3, 127.7, 125.9, 121.8, 117.3, 116.6, 116.3,
113.0, 109.1, 56.3, 56.2; HRMS (ESI) m/z
C20H16N2O2Na[M+Na]+ 339.1104, found 339.1118.
calcd for 4-(2,5-Dimethoxyphenyl)-6-(4-methylphenyl)nicotinonitrile
(3bn): White solid: Yield: 83% (54.8 mg); mp 122ꢀ124°C; Rf =
0.57(EtOAc:hexane = 1:4); IR (KBr)ν 2227, 1587, 1537, 1507,
1465, 1409, 1369, 1266, 1227 cmꢀ1; 1H NMR (400 MHz, CDCl3)
4-(4-Benzyloxy-3-methoxyphenyl)-6-phenylnicotinonitrile (3ao)
:White solid; Yield:86%( 67.4 mg); mp 132ꢀ134 °C; Rf = 0.35
(EtOAc:hexane = 1:4); IR (KBr) ν 2217, 1591, 1515, 1474, 1331,
δ8.93 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.31 (d, J = 8.0
Hz, 2H), 6.98ꢀ7.02 (m, 2H), 6.89 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H),
2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 154.0, 153.2,
150.7, 150.6, 141.0, 135.2, 130.0, 127.6, 126.0, 121.4, 117.5, 116.5,
116.4, 113.0, 108.8, 56.3, 56.2, 21.7; HRMS (ESI) m/z calcd for
C21H18N2O2Na [M+Na]+ 353.1260, found 353.1251.
1
1269, 1223,cmꢀ1; H NMR (400 MHz, CDCl3) δ8.96 (s, 1H), 8.06ꢀ
8.08 (m, 2H), 7.85 (s, 1H), 7.46ꢀ7.54 (m, 5H), 7.40 (t, J = 7.0 Hz,
2H), 7.31ꢀ7.35 (m, 1H), 7.25ꢀ7.26 (m, 1H), 7.18ꢀ7.21 (m, 1H), 7.04
(d, J = 8.2Hz, 1H), 5.24 (s, 2H), 3.99 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ160.7, 154.4, 152.9, 150.3, 150.2, 137.9, 136.8, 130.8,
129.3, 129.0, 128.4, 127.7, 127.5, 121.6, 120.2, 117.8, 114.2, 112.2, 4-(4-Chlorophenyl)-6-(4-methylphenyl)nicotinonitrile
(3bq):
106.5, 71.3, 56.6; HRMS (ESI) m/z calcd for C26H20N2O2Na White solid; Yield: 88%(53.5 mg); mp 136ꢀ138 °C; Rf = 0.80
[M+Na]+ 415.1417, found 415.1422.
(EtOAc:hexane = 1:4); IR (KBr)ν 2222, 1591, 1531, 1469, 1372,
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ8.97 (s, 1H), 7.98 (d, J = 8.0 Hz,
2H), 7.80 (s, 1H), 7.59ꢀ7.61 (m, 2H), 7.52ꢀ7.54 (m, 2H), 7.32 (d, J
= 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.0,
154.3, 151.9, 141.5, 136.9, 134.8, 134.7, 130.1, 130.0, 129.8, 127.6,
119.9, 117.3, 106.3, 21.7; HRMS (ESI) m/z calcd for C19H13ClN2Na
[M+Na]+ 327.0659, found 327.0659.
4-(4-Fluorophenyl)-6-phenylnicotinonitrile (3ap): White solid;
Yield: 90% (49.3 mg); mp 124ꢀ126°C; Rf = 0.75 (EtOAc:hexane =
1:4); IR (KBr) ν 2223, 1598, 1580, 1537, 1509, 1473, 1442, 1371,
1
1226, 1216, cmꢀ1; H NMR (400 MHz, CDCl3) δ8.99 (s, 1H), 8.07ꢀ
8.09 (m, 2H), 7.84 (s, 1H), 7.65ꢀ7.68 (m, 2H), 7.51ꢀ7.52 (m, 3H),
7.26 (t, J = 8.2 Hz, 2H);13C NMR (100 MHz, CDCl3) δ164.2(d, JCꢀ
F= 250 Hz), 160.9, 154.3, 152.2, 137.6, 132.3 (d, JCꢀF= 3.6 Hz), 4-(4-Bromophenyl)-6-(4-methylphenyl)nicotinonitrile
(3br):
131.0, 130.8 (d, JCꢀF= 8.0 Hz), 129.4, 127.7, 120.4, 117.3, 116.8( d, White solid; Yield: 84% (58.5 mg); mp 148ꢀ150 °C; Rf = 0.77
JCꢀF= 21.8 Hz), 106.7; HRMS (ESI) m/z calcd for C18H11FN2Na (EtOAc:hexane = 1:4); IR (KBr)ν 2220, 1589, 1527, 1488, 1466,
1
[M+Na]+ 297.0798, found 297.0796.
1368, 1280, 1252 cmꢀ1; H NMR (400 MHz, CDCl3) δ8.97 (s, 1H),
7.97 (d, J = 7.8 Hz, 2H), 7.80 (s, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.53
(d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 161.0, 154.3, 151.9, 141.5, 135.2, 134.8, 132.7,
130.2, 130.1, 127.6, 125.21, 119.8, 117.3, 106.2, 21.7; HRMS (ESI)
m/z calcd for C19H1379BrN2Na[M+Na]+ 371.0154, found 371.0151.;
4-(4-Chlorophenyl)-6-phenylnicotinonitrile (3aq): White solid;
Yield: 89% (51.6 mg); mp 132ꢀ134°C; Rf = 0.78 (EtOAc:hexane =
1:4); IR (KBr) ν 2222, 1534, 1493, 1470, 1441, 1369, 1243, cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ8.99 (s, 1H), 8.06ꢀ8.09 (m, 2H), 7.83 (s,
1H), 7.60ꢀ7.62 (m, 2H), 7.51ꢀ7.55 (m, 5H); 13C NMR (100 MHz,
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Journal Name
HRMS (ESI) m/z calcdfor C19H1381BrN2Na[M+Na]+ 371.0154, 6-(4-Bromophenyl)-4-(4-trifluoromethylphenyl)nicotinonitrile
found 371.0151.
(3hs):White solid; Yield: 87% (69.9 mg); mp 165ꢀ167 °C; Rf = 0.80
(EtOAc:hexane = 1:4); IR (KBr) ν 2221, 1587, 1536, 1476, 1368,
1331 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ9.03 (s, 1H), 7.97 (d, J =
8.2 Hz, 2H), 7.83ꢀ7.84 (m, 3H), 7.76ꢀ7.78 (m, 2H), 7.66 (d, J = 8.2
Hz, 2H);13C NMR (100 MHz, CDCl3)δ159.9, 154.3, 152.0, 139.5,
136.3, 132.8, 132.7, 132.4, 129.2, 129.2, 126.6, 126.6, 126.5, 126.5,
126.0, 125.3, 122.6, 120.2, 116.8, 107.1; HRMS (ESI) m/z calcd for
C19H1179BrF3N2[M+H]+ 403.0052, found 403.0052; HRMS (ESI)
m/z calcd for C19H1181BrF3N2[M+H]+ 405.0032, found 405.0036.
6-(4-Methoxyphenyl)-4-phenylnicotinonitrile (3cl): White solid:
Yield: 88% (50.4 mg); mp 122ꢀ124 °C; Rf = 0.67 (EtOAc:hexane =
1:4); IR (KBr) ν 2220, 1585, 1530, 1469, 1418, 1370, 1319, 1283,
1244 cmꢀ1;1 H NMR (400 MHz, CDCl3) δ8.93 (s, 1H), 8.05 (d, J =
8.8 Hz, 2H), 7.79 (s, 1H), 7.64ꢀ7.66 (m, 2H), 7.54ꢀ7.55 (m, 3H),
7.01 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3)δ162.0, 160.3, 154.2, 153.0, 136.3, 130.3, 130.2, 129.4,
129.2, 128.6, 119.5, 117.6, 114.7, 105.9, 55.7; HRMS (ESI) m/z
calcd for C19H14N2ONa [M+Na]+ 309.0998, found 309.0998.
4-Phenyl-6-(thiophen-2-yl)nicotinonitrile(3il): Pale yellow solid;
Yield: 80% (41.9 mg); mp116ꢀ118 °C; Rf = 0.75 (EtOAc:hexane =
1:4); IR (KBr) ν 2221, 1586, 1522, 1468, 1424, 1375, 1260, 1236
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ8.85 (s, 1H), 7.73ꢀ7.74 (m, 2H),
7.64ꢀ7.66 (m, 2H), 7.53ꢀ7.57 (m, 4H), 7.16 (t, J = 4.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ155.7, 154.3, 153.1, 143.3, 136.0, 130.7,
130.5, 129.5, 128.9, 128.6, 127.5, 118.7, 117.4, 106.2; HRMS (ESI)
m/z calcd for C16H10N2ONa [M+Na]+ 285.0457, found 285.0451.
6-(4-Chlorophenyl)-4-phenylnicotinonitrile(3fl):White
solid;
Yield: 82% (47.6 mg,); mp 133ꢀ135 °C; Rf = 0.77 (EtOAc:hexane =
1:4); IR (KBr)ν 2220, 1591, 1528, 1468, 1405, 1369, cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ8.98 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.84 (s,
1H), 7.65ꢀ7.67 (m, 2H), 7.56ꢀ7.57 (m, 3H), 7.49 (d, J = 8.5 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ159.5, 154.3, 153.5, 137.2, 136.1,
136.1, 130.6, 129.6, 129.5, 129.0, 128.6, 120.3, 117.3, 107.1;HRMS
(ESI) m/z calcd for C18H11ClN2Na [M+Na]+ 313.0503, found 4-(2,5-Dimethoxyphenyl)-6-(thiophen-2-yl)nicotinonitrile(3in):
313.0511.
Pale yellow solid; Yield: 75%(48.3 mg); mp 134ꢀ136°C; Rf = 0.55
(EtOAc:hexane = 1:4); IR (KBr)ν 2216, 1586, 1527, 1502, 1472,
1432, 1413, 1365, 1308, 1230 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ8.81 (s, 1H), 7.70 (s, 1H), 7.68 (d, J = 3.4 Hz, 1H), 7.51 (d, J = 4.7
Hz, 1H), 7.14 (t, J = 4.2 Hz, 1H), 6.99ꢀ7.03 (m, 2H), 6.87 (d, J =
2.4Hz, 1H), 3.82 (s, 6H); 13C NMR (100 MHz, CDCl3) δ155.5,
154.0, 153.2, 150.7, 150.7, 143.5, 130.4, 128.8, 127.3, 125.7, 119.9,
117.3, 116.6, 116.3, 113.0, 108.6, 56.3, 56.2;HRMS (ESI) m/z calcd
for C18H14N2O2SNa [M+Na]+ 345.0668, found 345.0650.
6-(2-Chlorophenyl)-4-phenylnicotinonitrile(3gl):White
solid;
Yield: 80% (46.4 mg); mp 132ꢀ134 °C; Rf = 0.78 (EtOAc:hexane =
1:4); IR (KBr)ν 3068, 2923, 2221, 1590, 1525, 1463, 1434, 1368,
1257, 1079, 1032, 900, 744, 694cmꢀ1; H NMR (400 MHz, CDCl3)
δ9.04 (s, 1H), 7.89 (s, 1H), 7.67ꢀ7.69 (m, 3H), 7.51ꢀ7.57 (m, 4H),
7.40ꢀ7.43 (m, 2H); 13C NMR (100 MHz, CDCl3) δ160.3, 154.1,
152.4, 137.8, 135.8, 132.4, 131.9, 131.1, 130.8, 130.6, 129.5, 128.8,
1
127.6, 125.3, 117.2, 107.3; HRMS (ESI) m/z
C18H11ClN2Na [M+Na]+ 313.0503, found 313.0498.
calcd for
3-Acetyl-4-(4-nitrophenyl)-6-phenylpyridine(3at): Light yellow
solid: Yield: 82% (52.2 mg); mp 137ꢀ139 °C; Rf
= 0.40
(EtOAc:hexane = 1:4); IR (KBr) ν 1682, 1590, 1526, 1507, 1479,
1444, 1350, 1271, 1234 cmꢀ1; 1H NMR (400 MHz, CDCl3)δ 9.06 (s,
1H), 8.34 (d, J = 7.6 Hz, 2Hz), 8.06ꢀ8.09 (m, 2H), 7.68 (s, 1H), 7.50ꢀ
7.54 (m, 5H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)δ199.2,
159.9, 150.2, 147.9, 147.7, 145.7, 137.6, 131.8, 130.3, 129.2, 129.0,
6-(4-Bromophenyl)-4-(2,5-dimethoxyphenyl)nicotinonitrile
(3hl):White solid; Yield: 80% (63.1 mg,); mp 130ꢀ132°C;Rf = 0.63
(EtOAc:hexane = 1:4); IR (KBr) ν 2218, 1587, 1533, 1499, 1472,
1
1444, 1357, 1310, 1228 cmꢀ1; H NMR (400 MHz, CDCl3)δ8.94 (s,
1H), 7.94 (d, J = 8.5 Hz, 2H), 7.80 (s, 1H), 7.63 (d, J = 8.5 Hz, 2H),
7.00ꢀ7.01 (m, 2H), 6.87ꢀ6.88 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H); 13
C
127.3, 123.9, 121.4, 29.8; HRMS (ESI) m/z
C19H15N2O3[M+H]+ 319.1077, found 319.1079.
calcd for
NMR (100 MHz, CDCl3) δ159.3, 154.0, 153.3, 151.0,150.7, 136.8,
132.5, 129.2, 125.7, 125.4, 121.5, 117.2, 116.7, 116.4, 113.0, 109.5,
56.3, 56.2; HRMS (ESI) m/z calcd for C20H15BrN2O2Na [M+Na]+ 3-Acetyl-4-(4-cyanophenyl)-6-phenylpyridine(3au):White solid;
417.0209, found 417.0200.
Yield: 80% (47.7 mg); mp132ꢀ134 °C; Rf = 0.38 (EtOAc:hexane =
1:4); IR (KBr) ν 2226, 1681, 1587, 1525, 1480, 1441, 1414, 1361,
1
1328, 1276, 1235 cmꢀ1; H NMR (400 MHz, CDCl3) δ9.02 (s, 1H),
6-(4-Bromophenyl)-4-(4-chlorophenyl)nicotinonitrile(3hq):White
8.05ꢀ8.07 (m, 2H), 7.76ꢀ7.78 (m, 2H), 7.66 (s, 1H), 7.48ꢀ7.51 (m,
4H), 7.46 (s, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ199.8,
160.1, 150.4, 148.2, 143.9, 138.0, 132.7, 132.3, 130.5, 129.3, 129.3,
127.6, 121.6, 118.6, 112.9, 30.2; HRMS (ESI) m/z calcd for
C20H14N2ONa [M+Na]+ 321.0998, found 321.1008.
solid; Yield: 86% (63.3 mg,); mp159ꢀ161°C; Rf
= 0.77
(EtOAc:hexane = 1:4); IR (KBr)ν 2220, 1588, 1530, 1492, 1466,
1400, 1366cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.96 (d,
J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.59ꢀ7.61
(m, 2H), 7.53ꢀ7.56 (m, 2H); 13C NMR (100 MHz, CDCl3) δ159.8,
154.4, 152.3, 137.1, 136.4, 134.4, 132.6, 130.0, 129.9, 129.2, 125.8,
120.0, 117.0, 107.0; HRMS (ESI) m/z
calcd for 3-Acetyl-4-(4-cyanophenyl)-6-(4-methylphenyl)pyridine(3bu):
C18H1179BrClN2[M+H]+ 368.9789, found 368.9794; HRMS (ESI) White solid; Yield: 82% (51.2 mg); mp136ꢀ138°C; Rf = 0.39
m/z calcd for C18H1181BrClN2[M+H]+ 370.9768, found 370.9773.
(EtOAc:hexane = 1:4); IR (KBr)ν, 2221, 1684, 1590, 1527, 1482,
1
1413, 1360, 1276, 1239, cmꢀ1; H NMR (400 MHz, CDCl3)δ9.00 (s,
1H), 7.96 (d, J = 8.2 Hz, 2H), 7.75ꢀ7.77 (m, 2H), 7.63 (s, 1H), 7.45ꢀ
10 | J. Name., 2012, 00, 1-3
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7.48 (m, 2H), 7.31 (d, J = 7.8 Hz, 2H), 2.42 (s, 3H), 2.35 (s, 3H); 13
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C
7.15ꢀ7.17 (m, 1H), 2.39 (s, 3H);13C NMR (100 MHz, CDCl3)δ198.4,
NMR (100 MHz, CDCl3) δ199.7, 160.2, 150.4, 148.2, 144.1, 140.9, 155.0, 150.5, 147.9, 145.6, 143.1, 131.2, 130.0, 129.1, 128.5, 126.7,
135.2, 132.7, 132.0, 130.1, 129.3, 127.5, 121.3, 118.6, 112.9, 30.2, 123.8, 119.6, 29.6; HRMS (ESI) m/z calcd for C17H13N2O3S[M+H]+
21.7; HRMS (ESI) m/z calcd for C21H16N2ONa [M+Na]+ 335.1155, 325.0642, found 325.0653.
found 335.1154.
3-Acetyl-4-(4-cyanophenyl)-6-(thiophen-2-yl)pyridine
(3iu):
3-Acetyl-4-(4-cyanophenyl)-6-(4-methoxyphenyl)pyridine
Light yellow solid; Yield: 74% (45.0 mg); mp 132ꢀ134 °C; Rf = 0.35
(3ct):White solid; Yield: 83% (54.5 mg); mp138ꢀ140 °C; Rf = 0.35 (EtOAc:hexane = 1:4); IR (KBr) ν 2219, 1682, 1587, 1521, 1480,
1
(EtOAc:hexane = 1:4); IR (KBr) ν 2224, 1735, 1673, 1607, 1588, 1426, 1357, 1305, 1278, 1235 cmꢀ1; H NMR (400 MHz, CDCl3) δ
1524, 1469, 1440, 1371, 1277, 1251cmꢀ1; 1H NMR (400 MHz, 8.91 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 3.2 Hz, 1H), 7.51ꢀ
CDCl3) δ8.99 (s, 1H), 8.03ꢀ8.05 (m, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.54 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.14ꢀ7.17 (m, 1H), 2.34 (s,
7.58 (s, 1H), 7.45ꢀ7.47 (m, 2H), 7.02 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H);13C NMR (100 MHz, CDCl3)δ198.8, 154.9, 150.4, 148.1, 143.6,
3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.6, 161.8, 143.2, 132.4, 131.5, 129.9, 128.9, 128.5, 126.6, 119.5, 118.3, 112.7,
159.8, 150.5, 148.2, 144.3, 132.7, 131.5, 130.5, 129.3, 129.1, 120.8, 29.7; HRMS (ESI) m/z calcd For C18H13N2OS[M+H]+ 305.0743,
118.7, 114.7, 112.8, 55.7, 30.1; HRMS (ESI) m/z calcd for found 305.0764.
C21H16N2O2Na[M+Na]+ 351.1104, found 351.1101.
The synthesis of intermediate 5: To a stirred solution of compound
3-Acetyl-4-(4-nitrophenyl)-6-(4-fluorophenyl)pyridine
(3et): 1a (39.4 mg, 0.2 mmol) and 2a (54.6 mg, 0.22 mmol) in 2ꢀMeTHF
Light yellow solid; Yield: 74% (49.8 mg); mp147ꢀ149 °C; Rf = 0.35 (1.0 mL) was added DABCO (33.6 mg, 0.3 mmol) at room
(EtOAc:hexane = 1:4); IR (KBr)ν 1682, 1591, 1533, 1508, 1480, temperature. Then the reaction mixture was heated at 70 °C for 30
1412, 1347, 1278, 1229 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ9.03 (s, min O2 atmosphere (monitored by TLC). After that, the reaction
1H), 8.33 (d, J = 8.5 Hz, 2H), 8.06ꢀ8.09 (m, 2H), 7.63 (s, 1H), 7.52 mixture was extracted with ethyl acetate (3 × 10 mL), washed with
(d, J = 8.7 Hz, 2H), 7.19 (t, J = 8.5 Hz, 2H), 2.39 (s, 3H); 13C NMR water and brine respectively, dried over Na2SO4. The combined
(100 MHz, CDCl3) δ199.4, 164.6(d, JCꢀF = 249 Hz), 159.1, organic phases were evaporated under reduced pressure to afford the
150.5,148.2, 148.1, 145.9, 134.1 (d, JCꢀF = 3.6.0 Hz), 132.1, 129.6(d, crude product which was purified through column chromatography
JCꢀF = 8.7 Hz) , 129.5, 124.2, 121.3, 116.4 (d , JCꢀF = 21.8 Hz), 30.1; through column chromatography over silicaꢀgel using a mixture of
HRMS (ESI) m/z calcd for C19H13FN2O3Na[M+Na]+ 359.0802, EtOAc/hexane (1:2, v/v) as the eluent. The intermediate 5 was fully
1
found 359.0802.
characterized by its spectroscopic data (IR, HNMR, 13C NMR and
HRMS).
3-Acetyl-4-(4-cyanophenyl)-6-(4-fluorophenyl)pyridine
(3eu):White solid; Yield: 74% (46.8 mg); mp142ꢀ144 °C; Rf = 0.45 Intermediate 5: Yield (90% combined yield of a mixture of
(EtOAc:hexane = 1:4); IR (KBr)ν 2219, 1683, 1593, 1528, 1481, diastereomer); IR (KBr) ν 1710, 1601, 1570, 1495, 1451, 1374,
1
1412, 1362, 1277, 1228 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ8.99 (s, 1302, 1273, 1200, cmꢀ1; H NMR (400 MHz, CDCl3) δ (mixture of
1H), 8.05ꢀ8.08 (m, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.61 (s, 1H), 7.47 diastereomer dr = 3:1) δ 7.84 (d, J = 7.7 Hz, 1.5H), 7.80 (d, J = 7.7
d, J = 8.0 Hz, 2H), 7.19 (t, J = 8.5 Hz, 2H), 2.35 (s, 3H); 13C NMR Hz, 0.5H), 7.73 (t, J = 7.2 Hz, 0.75H), 7.67 (t, J = 7.2 Hz, 0.25H),
(100 MHz, CDCl3) δ 199.7, 164.5(d, JCꢀF= 249.0 Hz), 159.0, 150.4, 7.59 (t, J = 7.6 Hz, 1.5H), 7.51 (t, J = 7.5 Hz, 0.5H), 7.33ꢀ7.40 (m,
148.3, 143.9, 134.2, 134.1 132.8, 132.3, 129.6, 129.5, 129.3, 128.5, 1.25H), 7.19ꢀ7.29 (m, 2.25H), 6.93 (d, J = 7.2 Hz, 1.5H), 6.59 (s,
128.4, 128.0, 127.9, 127.3, 125.9, 121.3, 118.6, 116.5, 116.2, 113.0, 0.75H), 6.56ꢀ6.57 (m, 1H), 6.35 (d, J = 3.2 Hz, 0.25H), 6.01 (s,
30.2; HRMS (ESI) m/z calcd for C20H14FN2O [M+H]+ 317.1085, 0.75H), 5.71 (s, 0.25H), 4.80 (s, 0.25H), 4.72 (s, 0.75H), 4.19ꢀ4.30
found 317.1079.
(m, 1.5H), 4.00ꢀ4.15 (m, 0.5H), 1.31 (t, J = 7.2Hz, 2.25H), 1.19 (t, J
7.2Hz, 0.75H); 13C NMR (100 MHz, CDCl3)
(major
=
δ
diastereomer) 178.4, 166.7, 138.2, 135.2, 132.5, 132.2, 130.1, 129.8,
129.5, 129.1, 128.5, 128.3, 89.0, 61.9, 49.4, 14.4; HRMS (ESI) m/z
calcd for C20H19NSO5Na [M+Na]+ 408.0876, found 408.0897.
3-Acetyl-4-(4-nitrophenyl)-6-(4-chlorophenyl)pyridine(3ft): Light
yellow solid; Yield: 77% (54.2 mg); mp151ꢀ153 °C; Rf = 0.45
(EtOAc:hexane = 1:4); IR (KBr) ν 1682, 1589, 1530, 1510, 1475,
1404, 1347, 1279, 1238cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 9.04 (s,
1H), 8.34 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.65 (s, 1H), One-pot
synthesis
of
ethyl
N-Boc-4,6-diphenyl-1,2-
7.47ꢀ7.53 (m, 4H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) dihydropyridine-3-carboxylate (8): A mixture of compound 1a
δ199.4, 158.9, 150.5, 148.3, 148.1, 145.8, 137.0, 136.3, 132.4, 129.6, (39.4 mg, 0.2 mmol), 2a (54.6 mg, 0.22 mmol), Boc2O (0.3 mmol)
129.5, 128.9, 124.2, 121.4, 30.2; HRMS (ESI) m/z calcd for and DABCO (33.6 mg, 0.3 mmol) in 2ꢀMeTHF (1.0 mL) was
C19H14ClN2O3[M+H]+ 353.0687, found 353.0673.
heated at 70 °C for 48h under inert atmosphere (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, dried over Na2SO4. The combined organic phases were
evaporated under reduced pressure to afford the crude product.
3-Acetyl-4-(4-nitrophenyl)-6-(thiophen-2-yl)pyridine (3it): Light
yellow solid; Yield: 76% (49.3 mg); mp 136ꢀ138 °C; Rf = 0.40
(EtOAc:hexane = 1:4); IR (KBr) ν 1681, 1588, 1529, 1506, 1425,
1
1347, 1278, 1239 cmꢀ1; H NMR (400 MHz, CDCl3)δ 8.95 (s, 1H),
Finally it was obtained in
a pure form 8 through column
8.33 (d, J = 8.4 H, 2H), 7.69 (d, J = 3.2 H, 1H), 7.49ꢀ7.55 (m, 4H),
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DOI: 10.1039/C7OB00240H
ARTICLE
Journal Name
Edink, M. Verheij, I. de Esch, L. Viteva, A. Loregian and M. Botta, J.
Med. Chem., 2016, 59, 2688.
(a) A.-Y. Guan, C.-L. Liu, X.-F. Sun, Y. Xie and M.-A. Wang, Bioorg.
chromatography over silicaꢀgel using a mixture of EtOAc/hexane
(1:4, v/v) as an eluent.
3
4
Med. Chem., 2015, 24, 342; (b) G. D. Henry, Tetrahedron, 2004, 60
6043.
,
Ethyl 1-tert-butoxycarbonyl-4,6-diphenyl-1,2-dihydropyridine-
3-carboxylate (8): Yield: 62% (51.0 mg); 1H NMR (400 MHz,
CDCl3) δ 7.40ꢀ7.42 (m, 2H), 7.33ꢀ7.37 (m, 6H), 7.27ꢀ7.29 (m, 2H),
6.00 (s, 1H), 4.79 (s, 2H), 4.03 (q, J = 7.2 Hz, 2H), 1.12 (s, 9H),
1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8,
153.0, 146.0, 144.5, 139.6, 138.1, 128.9, 128.5, 128.2, 128.1, 128.0,
127.1, 117.5, 117.5, 81.9, 60.6, 45.5, 27.9, 14.0; HRMS (ESI) m/z
calcd for C25H27NO4Na[M+Na]+ 428.1832, found 428.183.
(a) Functional Organic Materials, ed. T. J. J. Müller and U. H. F. Bunz,
Wiley-VCH, Weinheim, 2007; (b) H. Sasabe and J. Kido, Chem.
Mater., 2011, 23, 621.
Y.-T. Chan, C. N. Moorefield, M. Soler and G. R. Newkome, Chem.
Eur. J., 2010, 16, 1768.
(a) F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90, 2265; (b) M. C.
Bagley, C. Glover and E. A. Merritt, Synlett, 2007, 16, 2459; (c) M. C.
Bagley, J. W. Dale and J. Bower, Chem. Commun., 2002, 1682; (d) M.
C. Bagley, K. Chapaneri, J. W. Dale, X. Xiong and J. Bower, J. Org.
Chem., 2005, 70, 1389; (e) A.-L. Blayo, S. L. Meur, D. Grée and R.
Grée, Adv. Synth. Catal., 2008, 350, 471.
5
6
Synthesis of 2-(4,6-diphenylpyridin-3-yl)-[1,2,4]triazolo[1,5-
a]pyridine(9): A mixture of compound 3al (0.2 mmol, 52.0 mg), 2ꢀ
aminopyridine (0.24 mmol, 24 mg), CuBr (0.01 mmol, 1.5 mg),
1,10ꢀphenanthroline (0.01 mmol, 1.8 mg) and ZnI2 (0.02 mmol 6.4
mg) 1,2ꢀdichlorobenzene (0.4 ml) was stirred at 130 ° C for 18 h.
After cooling to room temperature, the reaction was diluted with
EtOAc and filtered through celite. The filtrate was concentrated and
purified by column chromatography (eluent: EtOAc:hexane = 1:3)
on silica gel to afford compound 9.
7
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12945; (b) F. Liéby-Muller, C. Allais, T. Constantieux and J. Rodriguez,
Chem. Commun., 2008, 4207; (c) C. Allais, F. Liéby-Muller, J.
Rodriguez and T. Constantieux, Eur. J. Org. Chem., 2013, 4131; (d) N.
R. Gade, V. Devendram, M. Pal and J. Iqbal, Chem. Commun., 2013,
49, 7926; (e) Z. Song, X. Huang, W. Yi and W. Zhang, Org. Lett., 2016,
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Karanjai and A. Thomas, J. Org. Chem., 2016, 81
, 1645; (h) C. R.
Reddy, S. A. Panda and M. D. Reddy, Org. Lett., 2015, 17, 896; (i) A.
Prechter, G. Henrion, P. F. dit Bel and Gagosz, F. Angew. Chem., Int.
Ed., 2014, 53, 4959; (j) D. Tejedor, G. Méndez-Abt and F. García-
Tellado, Eur. J. Org. Chem., 2010, 6582; (k) D. Tejedor, G. Méndez-
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2-(4,6-Diphenylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine(9):
White solid; Yield 81% (56.3 mg); mp 173ꢀ175 °C; Rf = 0.20
(EtOAc:hexane = 1:4); IR (KBr): ν 1632, 1589, 1576, 1556, 1500,
1456, 1425, 1386, 1356, 1327, 1305, 1259, 1211; 1H NMR (400
MHz, CDCl3): δ 9.21 (s, 1H), 8.49 (d, J = 6.4 Hz, 1H), 8.11 (d, J =
7.6 Hz, 2H), 7.82 (s, 1H), 7.68ꢀ7.71 (m, 1H), 7.43ꢀ7.52 (m, 4H),
7.30ꢀ7.38 (m, 5H), 6.97ꢀ7.00 (m, 1H); 13C NMR (100 MHz, CDCl3):
δ 162.5, 158.1, 151.7, 151.1, 150.0, 139.1, 138.8, 129.4, 129.3, 128.8
(2C), 128.3, 128.2, 128.1, 127.2, 124.3, 121.8, 116.6, 113.7; HRMS
(ESI) m/z calcd for C23H17N4[M+H]+ : 349.1448, found 349.1475.
C.-M. Park, Chem. Sci., 2014,
Hoarau and F. Marsais, Org. Lett., 2006,
5
, 2347; (n) N. Robert, A.-L. Bonneau, C.
8
, 6071; (o) J. Yu, K. H. Kim,
H. J. Lee and J. N. Kim, Bull. Korean Chem. Soc., 2013, 34, 3027; (p)
K. H. Kim, S.H. Kim, H. J. Lee and J. N. Kim, Adv. Synth. Catal., 2013,
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2009, 50, 6651; (s) S. Hirai, Y. Horikawa, H. Asahara and N. Nishiwaki,
Chem. Commun., 2017, 53, 2390.
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D. Majee, S. Biswas, S. M. Mobin and S. Samanta, J. Org. Chem.,
2016, 81, 4378.
(a) M. Baidya, G. Y. Remennikov, P. Mayer and H. Mayr, Chem. Eur.
Acknowledgements
The authors thank SERB (Project No. SB/S1/OCꢀ19/2013) and
CSIR (Project No. 02(0273)/16/EMRꢀII) research grants for their
generous financial supports. D. Majee and S. Biswas are also
thankful to CSIR and UGC for their fellowships respectively.
J., 2010, 16, 1365; (b) Y. Wei and M. Shi, Chem. Rev. 2013, 113,
6659.207
10 (a) D. Majee, S. M. Mobin and S. Samanta, RSC. Adv., 2013, 3, 11502;
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Lett., 2014, 55, 4553.
11 Hantzsch, A. Ber. Dtsch. Chem. Ges., 1881, 14, 1637.
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Rivalti and D. T. McQuade, J. Org. Chem., 2015, 80, 8583; (b) A. R.
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Notes and references
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12 | J. Name., 2012, 00, 1-3
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ARTICLE
17 (a) M. Shi, J.-K. Jiang and C.-Q. Li, Tetrahedron Lett., 2002, 43, 127;
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49392.
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Organic & Biomolecular Chemistry
Page 14 of 15
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DOI: 10.1039/C7OB00240H
Domino reaction of cyclic sulfamidate imines with Morita-Baylis-
Hillman acetates promoted by DABCO: a metal-free approach to
functionalized nicotinic acid derivatives
Debashis Majee, Soumen Biswas, Shaikh M. Mobin and Sampak Samanta*
A series of 3-carboxylate/cyano/acetyl-4,6-diarylpyridines have been prepared in good to excellent yields via a domino reaction
of cyclic sulfamidate imines with MBH acetates of acrylate/acrylonitrile/MVK in 2-MeTHF promoted by DABCO under O2
atmosphere.

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DOI: 10.1039/C7OB00240H
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