Synthesis of Functionalized Pyridines via Cu(II)-Catalyzed One-Pot Cascade Reactions of Inactivated Saturated Ketones with Electron-Deficient Enamines

Article abstract of DOI:10.1021/acs.joc.7b01901

In this paper, a novel and efficient synthesis of 3-acylpyridines and pyridine-3-carboxylates through the oxidative one-pot sequential reactions of inactivated saturated ketones with electron-deficient enamines is presented. Mechanistically, the formation of the title compounds involves the in situ formation of an enone intermediate through an oxidative dehydrogenation of the saturated ketone substrate, followed by its [3+3] annulation with β-enaminone or β-enaminoester via a cascade process, including Michael addition, aldol type condensation, and oxidative aromatization.

Full text of DOI:10.1021/acs.joc.7b01901

Note
pubs.acs.org/joc
Synthesis of Functionalized Pyridines via Cu(II)-Catalyzed One-Pot
Cascade Reactions of Inactivated Saturated Ketones with Electron-
Deficient Enamines
Guang Chen, Ze Wang, Xinying Zhang,* and Xuesen Fan*
School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of
Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China
S
* Supporting Information
ABSTRACT: In this paper, a novel and efficient synthesis of
3-acylpyridines and pyridine-3-carboxylates through the
oxidative one-pot sequential reactions of inactivated saturated
ketones with electron-deficient enamines is presented.
Mechanistically, the formation of the title compounds involves
the in situ formation of an enone intermediate through an
oxidative dehydrogenation of the saturated ketone substrate,
followed by its [3+3] annulation with β-enaminone or β-
enaminoester via a cascade process, including Michael addition,
aldol type condensation, and oxidative aromatization.
Scheme 1. Various Versions of Pyridine Synthesis from
Electron-Deficient Enamines
yridine is an essential building block and privileged scaffold
Pembedded in numerous natural products, pharmaceuticals,
functional materials, and fine chemicals.1,2 Many pyridine
derivatives are also efficient bases and ligands routinely utilized
in chemical catalysis.3 In particular, pyridines bearing one or
more carbonyl unit(s) have been frequently used as versatile
substrates in the preparation of fused N-heterocycles and other
structurally advanced organic molecules.4 Unsurprisingly, the
tremendous importance of pyridine derivatives has stimulated
enormous efforts in developing efficient and practical methods
for their preparation.5,6
As the unique chimera of “enamine” and “enone”, electron-
deficient enamines (EDEs) such as β-enaminones and β-
enaminoesters not only possess the ambident nucleophilicity of
enamines but also have the ambident eletrophilicity of enones.
Because of their diverse and rich reactivity, EDEs are valuable
substrates in the preparation of various N-heterocycles and
functionalized benzenes.7 Specifically, a number of elegant
methods for the preparation of functionalized pyridines by
using EDEs as the building blocks have been reported, which
mainly include condensation of primary enaminone/esters with
alkynone (Scheme 1, eq 1),8a reaction of tertiary enaminones
with enaminone/esters (Scheme 1, eq 2),8b cyclization of the in
situ-generated primary enaminones/esters with Mannich bases
(Scheme 1, eq 3),8c FeCl3-mediated condensation of
enaminoesters with enones (Scheme 1, eq 4),8d and many
others.8e−i Despite these advances, the development of more
flexible and operationally simple methods for preparing
functionalized pyridines starting from readily available and
economical substrates remains a challenging task in organic
synthesis.
Meanwhile, the oxidative dehydrogenation of inactivated
saturated ketones (IASKs) to give the corresponding enone
derivatives is currently of interest because of the cheap price
and rich source of IASKs, and the versatile reactivity and
diverse utility of the enone products.9 Moreover, some
elegantly designed one-pot cascade procedures combining the
oxidative dehydrogenation of IASKs with other kinds of
transformations leading to the formation of complex synthetic
Received: July 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01901
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
targets have also been realized in previous studies.10 Inspired by
those pioneering contributions and as a continuation of our
own interest in this aspect,11 we have designed an alternative
synthesis of diversely functionalized pyridines from simple
substrates by taking advantage of the direct C(sp3)−H bond
oxidative functionalization and the rich reactivity of EDEs
(Scheme 1, eq 5). Herein, we report the results we obtained in
this regard.
Our study was initiated by choosing propiophenone (1a) and
3-amino-1-phenylbut-2-en-1-one (2a) as model substrates and
treating them with Cu(OAc)2, TEMPO (2,2,6,6-tetramethylpi-
peridine-N-oxyl), and bpy (2,2′-bipyridine) in toluene at 120
°C for 20 h. The desired (2-methyl-6-phenylpyridin-3-
yl)(phenyl)methanone (3a) was obtained in 68% yield
(Table 1, entry 1). To improve the efficiency, various solvents,
when o-iodoxybenzoic acid (IBX), tert-butyl peroxide (TBP),
tert-butyl hydroperoxide (TBHP), or 4-hydroxy-2,2,6,6-tetra-
methylpiperidinooxy (TEMPOH) was used to replace
TEMPO, no improvement in the yield of 3a was observed
(entries 15−18). Running the reaction at a temperature above
or below 120 °C did not result in a better yield of 3a (entry 19
or 20, respectively). Prolonging the reaction period to 24 h
gave 3a in a yield similar to that of 20 h (entry 21). On the
other hand, changing the reaction period from 20 to 16 h
showed an adverse effect (entry 22).
With the established optimal reaction conditions, the
suitability of a range of IASKs (1) for this new reaction was
studied by using 2a as a model substrate. It was first observed
that several propiophenones reacted smoothly with 2a to give
3a−k in good to excellent yields. Meanwhile, various functional
groups such as methyl, methoxy, fluoro, chloro, bromo, or
trifluoromethyl attached on the phenyl ring were well tolerated.
Notably, the electronic nature of the phenyl unit did not show
any obvious effect on the outcome of this reaction in that
substrates bearing electron-withdrawing group(s) and those
with electron-donating group(s) afforded the corresponding
products in almost equally good efficiencies. Interestingly, 2-
propionylthiophene took part in this reaction smoothly to give
3l in 82% yield. Two aliphatic ketones, 1-cyclohexylpropan-1-
one and 2-methylpentan-3-one, were compatible, although the
yields of 3m and 3n were lower. 3-Phenylpropanal could also
react with 2a to give 3o. As for the scope of enaminones (2), in
addition to those derived from 1-phenylbutane-1,3-diones,
enaminones (2) prepared from 1,3-diphenylpropane-1,3-dione,
pentane-2,4-dione, and cyclohexane-1,3-dione could also react
with various ketones (1) to give 3p−t in moderate to good
yields (Table 2).
Accomplishing the efficient synthesis of 3-acylpyridines (3)
from 1 and 2 encouraged us to extend the scope of EDEs from
enaminones (2) to enaminoesters (4), from which the
biologically and synthetically significant pyridine-3-carboxy-
lates12,13 (5) should be obtained. Thus, a mixture of 1a and
ethyl 3-amino-3-phenylacrylate (4a) was subjected to the
standard reaction conditions used for the preparation of 3
(Table 1, entry 5). To our delight, the desired ethyl 2,6-
diphenylnicotinate (5a) was formed in 76% yield. Then, the
suitability of different IASKs (1) was studied by using 4a as a
model substrate. It turned out that propiophenones with
various functional groups attached on the phenyl ring, 2-
propionylthiophene, 1-cyclohexylpropan-1-one, and 2-methyl-
pentan-3-one, took part in this reaction smoothly to afford 5a−
g in moderate to good yields (Table 3). In addition, 3-
phenylpropanal worked well to give 5h in 32% yield. In
addition to 4a, several other enaminoesters (4) were also tried
using 1a as a model substrate. It was found that a series of 3-
phenyl-substituted enaminoesters bearing a methyl, methoxy,
chloro, or fluoro unit on the phenyl ring reacted with 1a
efficiently to give 5i−l in 70−81% yields. Interestingly, the
reaction of ethyl 3-amino-3-(thiophen-2-yl)acrylate proceeded
smoothly to give 5m in 61% yield. In addition to 3-
arylenaminoesters, 3-alkyl-substituted enaminoesters were
found to be suitable partners for this reaction to give 5n−p
in moderate yields.
a
Table 1. Optimization Studies for the Synthesis of 3a
yield
b
entry
catalyst
oxidant (equiv)
solvent
T (°C)
(%)
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
CuBr2
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
−
toluene
PhCl
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
110
120
120
68
66
46
43
77
60
53
52
43
−
2
3
DCE
4
CH3CN
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
5
6
7
8
9
CuCl2
10
11
12
13
14
15
16
17
18
19
20
−
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
−
TEMPO (2)
TEMPO (0.5)
TEMPO (0.2)/O2
IBX (1)
78
42
18
8
TBP (1)
7
TBHP (1)
trace
69
75
66
76
68
TEMPOH (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
c
21
d
22
a
Reaction conditions: 0.6 mmol of 1a, 0.5 mmol of 2a, 0.05 mmol of
b
catalyst, 0.1 mmol of bpy, oxidant, 2 mL of solvent, air, 20 h. Isolated
yield. Period of 24 h. Period of 16 h.
c
d
including PhCl, DCE, CH3CN, DMF, and DMSO, were used
(entries 2−6, respectively). Among them, DMF was the most
efficient and gave 3a in 77% yield (entry 5). Then, Cu(OTf)2,
CuBr2, and CuCl2 were tried as the catalyst, and they were
found to be less efficient than Cu(OAc)2 (entries 7−9,
respectively, vs entry 5). Subsequent studies showed that in
the absence of either Cu(II) salt or TEMPO, the formation of
3a was not observed (entry 10 or 11, respectively).
Furthermore, increasing the amount of TEMPO from 1 to 2
equiv did not improve the yield of 3a obviously (entry 12),
while reducing this amount to 0.5 equiv resulted in diminished
efficiency (entry 13). A combination of a catalytic amount of
TEMPO with O2 gave a low yield of 3a (entry 14). Moreover,
On the basis of the aforementioned observations and
previous reports,7,10 a tentative mechanism accounting for the
formation of 3a is proposed in Scheme 2. First, an oxidative
dehydrogenation occurs with 1a to give enone A, which then
undergoes a conjugate addition with 2a to afford adduct B.
B
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Note
a b
,
(Scheme 2). Meanwhile, an alternative pathway involving the
formation of an imine (E) through the condensation between A
and 2a, oxidative dehydrogenation of E to give F, followed by a
six-π-electron cyclization of F to give 3a could not be
eliminated at this stage.
Table 2. Substrate Scope for the Synthesis of 3
To verify the reaction mechanism as described in Scheme 2,
pre-prepared enone A was treated with 2a under standard
conditions to give 3a in 85% yield (Scheme 3). This result
indicated that enone A should be a key intermediate in the
formation of 3a from 1a and 2a.
Notably, the nucleophilic amino group of 2a has the
potential to be added via an aza-Michael addition onto the in
situ-formed enone A to give intermediate M,7 from which 3a′,
the regioisomer of 3a, might be formed through an intra-
molecular enamine−carbonyl condensation followed by an
oxidative aromatization via intermediates N and O (Scheme 4).
In our study, however, the formation of 3a′ was not observed,
indicating this reaction is highly regioselective.
In addition, many azafluoren(on)e derivatives are endowed
with significant biological and medicinal activities.14 In spite of
their importance, efficient methods for their preparation are still
limited.15 To provide an alternative synthetic approach to 4-
azafluoren(on)e derivatives and to showcase the usability of the
products obtained, 3p was first treated with NaBH4 in
methanol to give 6. Treatment of 6 with TfOH led to the
formation of 7 (Scheme 5, eq 1). Next, 5a was treated with
polyphosphoric acid (PPA) to give 8a in an excellent yield of
87% (Scheme 5, eq 2). Similarly, 8b could be obtained from 5g
in 78% yield. Given the high efficiency and easy-to-obtain
substrates, these transformations hold great potential in the
synthesis of azafluorene and azafluorenone derivatives.
Finally, to demonstrate the newly developed method for the
preparation of functionalized pyridines is suitable for large-scale
synthetic missions, the preparation of 3a was performed on an
enlarged scale of 5 mmol. It turned out that the corresponding
reaction proceeded smoothly to afford 3a in 65% yield (Scheme
6).
a
Reaction conditions: 0.6 mmol of 1, 0.5 mmol of 2, 0.05 mmol of
Cu(OAc)2, 0.1 mmol of bpy, 0.5 mmol of TEMPO, 2 mL of DMF, air,
120 °C, 20 h. Isolated yield.
b
a,b
Table 3. Substrate Scope for the Synthesis of 5
In summary, we have developed a novel and easy-to-run
synthetic approach toward diversely functionalized pyridines
through Cu-catalyzed one-pot cascade reactions of inactivated
saturated ketones with electron-deficient enamines via inert
C(sp3)−H bond functionalization under an air atmosphere. To
the best of our knowledge, this should be the first example in
which 3-acylpyridines and pyridine-3-carboxylates are directly
prepared from inactivated ketones and β-enaminone or β-
enaminoester. With notable features such as a broad substrate
scope, simple reaction conditions, excellent regioselectivity, and
atom economy, the synthetic protocol developed herein is
expected to find wide applications in related areas.
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise noted, all of the commercial
reagents were used without further purification. The solvents were
dried prior to use. β-Enaminones (2) and β-enaminoesters (4) were
prepared on the basis of a literature procedure.16 Melting points were
recorded with a micro melting point apparatus and are uncorrected.
1
The H NMR spectra were recorded at 400 or 600 MHz. The 13C
a
Reaction conditions: 0.6 mmol of 1, 0.5 mmol of 4, 0.05 mmol of
NMR spectra were recorded at 100 or 150 MHz. Chemical shifts are
expressed in parts per million (δ) downfield from the internal standard
tetramethylsilane and are reported as s (singlet), d (doublet), t
(triplet), dd (doublet of doublets), m (multiplet), br s (broad singlet),
etc. Coupling constants J are given in hertz. High-resolution mass
spectra (HRMS) were obtained in ESI mode by using a MicrOTOF
mass spectrometer. The conversion of starting materials was
Cu(OAc)2, 0.1 mmol of bpy, 0.5 mmol of TEMPO, 2 mL of DMF, air,
120 °C, 20 h. Isolated yield.
b
Isomerization of B affords B′. Next, an intramolecular
nucleophilic addition occurs with B′ to afford dihydropyridine
D via C. Finally, an oxidative dehydrogenation of D affords 3a
C
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Note
Scheme 2. Plausible Reaction Pathways Accounting for the Formation of 3a
under reduced pressure. The residue was purified by column
chromatography on silica gel with a petroleum ether/ethyl acetate
(20:1) eluent to give 3a. 3b−t and 5a−p were obtained in a similar
manner.
Scheme 3. Control Experiment
(2-Methyl-6-phenylpyridin-3-yl)(phenyl)methanone (3a). Eluent:
petroleum ether/ethyl acetate (20:1); white solid (105 mg, 77%); mp
70−71 °C (lit.8c 73−74 °C); H NMR (400 MHz, CDCl3) δ 2.63 (s,
1
3H), 7.42−7.50 (m, 5H), 7.59−7.64 (m, 2H), 7.70 (d, J = 8.4 Hz,
1H), 7.82 (d, J = 7.6 Hz, 2H), 8.07 (d, J = 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 23.9, 117.0, 127.3, 128.8, 128.9, 129.6, 130.1,
132.1, 133.6, 137.5, 138.8, 157.1, 158.2, 197.3; MS m/z 274 [M + H]+.
[2-Methyl-6-(p-tolyl)pyridin-3-yl](phenyl)methanone (3b). Elu-
ent: petroleum ether/ethyl acetate (20:1); yellow solid (101 mg,
Scheme 4. Theoretically Plausible but Not Observed
Formation of 3a′
1
70%); mp 80−81 °C; H NMR (600 MHz, CDCl3) δ 2.39 (s, 3H),
2.62 (s, 3H), 7.27 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.58 (d,
J = 7.2 Hz, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H),
7.97 (d, J = 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 21.4, 24.0,
116.6, 127.2, 128.8, 129.7, 130.1, 131.7, 133.6, 136.0, 137.5, 137.6,
139.7, 157.1, 158.2, 197.3; HRMS calcd for C20H18NO 288.1383 [M +
H]+, found 288.1388.
Scheme 5. Synthesis of 4-Azafluorene and 4-Azafluorenones
[6-(4-Methoxyphenyl)-2-methylpyridin-3-yl](phenyl)methanone
(3c). Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (121
1
mg, 80%); mp 81−82 °C; H NMR (600 MHz, CDCl3) δ 2.62 (s,
3H), 3.85 (s, 3H), 7.00 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H),
7.55 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.66 (d, J = 7.8 Hz,
1H), 7.81 (d, J = 7.2 Hz, 2H), 8.04 (d, J = 7.8 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 23.9, 55.4, 114.2, 116.0, 128.6, 128.7, 130.0,
131.2, 131.3, 133.4, 137.5, 137.6, 157.1, 157.8, 161.0, 197.3; HRMS
calcd for C20H18NO2 304.1332 [M + H]+, found 304.1334.
[6-(4-Fluorophenyl)-2-methylpyridin-3-yl](phenyl)methanone
(3d). Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (122
1
mg, 84%); mp 77−78 °C; H NMR (600 MHz, CDCl3) δ 2.62 (s,
3H), 7.15 (t, J = 7.8 Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H), 7.56−7.61 (m,
2H), 7.68 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 7.2 Hz, 2H), 8.06 (t, J = 6.6
Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 23.9, 115.8 (2JC−F = 21.9
Hz), 116.6, 128.8, 129.2 (3JC−F = 8.7 Hz), 130.0, 132.0, 133.6, 134.9
(4JC−F = 2.3 Hz), 137.4, 137.5, 157.0, 157.1, 163.9 (1JC−F = 248.3 Hz),
197.1; 19F NMR (376 MHz, CDCl3) δ −112.09; HRMS calcd for
C19H15FNO 292.1132 [M + H]+, found 292.1128.
Scheme 6. Gram-Scale Synthesis of 3a
[6-(4-Chlorophenyl)-2-methylpyridin-3-yl](phenyl)methanone
(3e). Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (117
1
mg, 76%); mp 105−106 °C; H NMR (600 MHz, CDCl3) δ 2.61 (s,
3H), 7.43−7.49 (m, 4H), 7.58−7.61 (m, 2H), 7.70 (d, J = 6.6 Hz,
1H), 7.81 (d, J = 7.2 Hz, 2H), 8.01 (d, J = 7.8 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 23.9, 116.8, 128.6, 128.9, 129.1, 130.1, 132.3,
133.7, 135.8, 137.1, 137.4, 137.5, 156.8, 157.2, 197.0; HRMS calcd for
C19H15ClNO 308.0837 [M + H]+, found 308.0833.
monitored by thin layer chromatography (TLC) using silica gel plates
(silica gel 60 F254 0.25 mm), and components were visualized by
observation under ultraviolet light (254 and 365 nm).
Experimental Procedures. Typical Procedure for the Synthesis
of 3a and Spectroscopic Data of 3a−t and 5a−p. To a 15 mL
reaction tube equipped with a stir bar containing a solution of 3-
amino-1-phenylbut-2-en-1-one (2a, 80.6 mg, 0.5 mmol) in DMF (2
mL) were added propiophenone (1a, 80 μL, 0.6 mmol), Cu(OAc)2
(9.1 mg, 0.05 mmol), 2,2′-bipyridine (15.6 mg, 0.1 mmol), and
TEMPO (78.1 mg, 0.5 mmol). The tube was then sealed, and the
mixture was stirred at 120 °C under an air atmosphere for 20 h. After
the mixture had been cooled to room temperature, the reaction was
quenched with water, and the mixture was extracted with ethyl acetate
(3 × 8 mL). The combined organic layers were washed with water (5
mL) and brine (5 mL), dried over anhydrous Na2SO4, and evaporated
[6-(4-Bromophenyl)-2-methylpyridin-3-yl](phenyl)methanone
(3f). Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (112
1
mg, 64%); mp 115−116 °C; H NMR (600 MHz, CDCl3) δ 2.61 (s,
3H), 7.48 (t, J = 7.2 Hz, 2H), 7.60−7.61 (m, 4H), 7.70 (d, J = 7.8 Hz,
1H), 7.81 (d, J = 7.2 Hz, 2H), 7.95 (d, J = 7.8 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 23.9, 116.7, 124.2, 128.8, 128.9, 130.1, 132.1,
132.4, 133.7, 137.3, 137.5, 137.6, 156.8, 157.2, 197.0; HRMS calcd for
C19H15BrNO 352.0332 [M + H]+, found 352.0359.
{2-Methyl-6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}(phenyl)-
methanone (3g). Eluent: petroleum ether/ethyl acetate (20:1);
D
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1
yellow solid (114 mg, 67%); mp 72−73 °C; H NMR (600 MHz,
CDCl3) δ 2.63 (s, 3H), 7.49 (t, J = 7.2 Hz, 2H), 7.62 (t, J = 7.2 Hz,
1H), 7.67 (d, J = 7.8 Hz, 1H), 7.73−7.74 (m, 3H), 7.83 (d, J = 7.2 Hz,
2H), 8.18 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 23.8,
117.4, 124.2 (1JC−F = 270.8 Hz), 125.9 (3JC−F = 3.5 Hz), 127.6, 128.9,
130.1, 131.3 (2JC−F = 32.0 Hz), 133.0, 133.9, 137.2, 137.5, 142.1,
156.4, 157.3, 196.9; 19F NMR (376 MHz, CDCl3) δ −62.63; HRMS
calcd for C20H15F3NO 342.1100 [M + H]+, found 342.1094.
(2-Methyl-4-phenylpyridin-3-yl)(phenyl)methanone (3o). Eluent:
petroleum ether/ethyl acetate (20:1); yellow solid (38 mg, 28%); mp
112−113 °C; 1H NMR (400 MHz, CDCl3) δ 2.48 (s, 3H), 7.21−7.26
(m, 6H), 7.30 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.60 (d, J =
8.0 Hz, 2H), 8.65 (d, J = 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
23.0, 121.7, 128.46, 128.48, 128.58, 128.64, 129.3, 133.6, 133.7, 136.9,
137.8, 147.8, 149.5, 155.2, 198.1; HRMS calcd for C19H16NO
274.1226 [M + H]+, found 274.1244.
(2,6-Diphenylpyridin-3-yl)(phenyl)methanone (3p). Eluent: petro-
leum ether/ethyl acetate (20:1); yellow solid (126 mg, 75%); mp
102−103 °C (lit.6c 101.4−103.1 °C); 1H NMR (400 MHz, CDCl3) δ
7.16−7.24 (m, 5H), 7.35−7.40 (m, 1H), 7.41−7.48 (m, 3H), 7.62 (dd,
J1 = 8.0 Hz, J2 = 1.6 Hz, 2H), 7.66−7.68 (m, 2H), 7.77 (d, J = 8.0 Hz,
1H), 7.87 (d, J = 8.0 Hz, 1H), 8.16−8.18 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 117.8, 127.3, 128.25, 128.33, 128.9, 129.5, 129.7,
129.9, 132.6, 133.2, 136.9, 138.3, 138.5, 139.5, 157.3, 158.1, 197.5; MS
m/z 336 [M + H]+.
Phenyl(6-phenyl-[2,3′-bipyridin]-5-yl)methanone (3q). Eluent:
petroleum ether/ethyl acetate (20:1); yellow solid (134 mg, 80%);
mp 119−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.24−7.28 (m, 3H),
7.31 (t, J = 8.0 Hz, 2H), 7.43−7.46 (m, 2H), 7.61−7.63 (m, 2H),
7.69−7.71 (m, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H),
8.51 (dt, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 8.70 (dd, J1 = 4.4 Hz, J2 = 1.2
Hz, 1H), 9.37 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
118.0, 123.7, 128.37, 128.45, 129.1, 129.4, 129.9, 133.3, 133.5, 134.0,
134.7, 136.6, 138.5, 139.1, 148.6, 150.5, 155.5, 157.6, 197.2; HRMS
calcd for C23H17N2O 337.1335 [M + H]+, found 337.1336.
1-(2-Methyl-6-phenylpyridin-3-yl)ethanone (3r). Eluent: petrole-
um ether/ethyl acetate (20:1); yellow solid (67 mg, 64%); mp 87−88
°C (lit.6c 90.3−91.5 °C); 1H NMR (400 MHz, CDCl3) δ 2.60 (s, 3H),
2.84 (s, 3H), 7.43−7.49 (m, 3H), 7.62 (d, J = 8.0 Hz, 1H), 8.01−8.06
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 25.4, 29.3, 117.3, 127.3,
128.9, 129.8, 130.6, 138.1, 138.4, 158.61, 158.63, 200.0; MS m/z 212
[M + H]+.
[6-(3-Methoxyphenyl)-2-methylpyridin-3-yl](phenyl)methanone
(3h). Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (103
1
mg, 68%); mp 89−90 °C; H NMR (600 MHz, CDCl3) δ 2.53 (s,
3H), 3.79 (s, 3H), 6.89 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H),
7.38 (t, J = 7.2 Hz, 2H), 7.51 (t, J = 7.8 Hz, 3H), 7.57−7.60 (m, 2H),
7.72 (d, J = 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 23.8, 55.4,
112.6, 115.4, 117.1, 119.6, 128.7, 129.9, 130.0, 132.2, 133.6, 137.36,
137.39, 140.2, 157.0, 157.9, 160.2, 197.2; HRMS calcd for C20H18NO2
304.1322 [M + H]+, found 304.1332.
[6-(3-Chlorophenyl)-2-methylpyridin-3-yl](phenyl)methanone
(3i). Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (118
1
mg, 77%); mp 78−79 °C; H NMR (400 MHz, CDCl3) δ 2.62 (s,
3H), 7.39−7.40 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.61 (t, J = 8.0 Hz,
2H), 7.70 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.92 (s, 1H),
8.10 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 23.8, 117.0, 125.3,
127.4, 128.8, 129.5, 130.05, 130.14, 132.6, 133.7, 135.0, 137.3, 137.5,
140.5, 156.5, 157.2, 197.0; HRMS calcd for C19H15ClNO 308.0837 [M
+ H]+, found 308.0847.
[6-(3-Bromophenyl)-2-methylpyridin-3-yl](phenyl)methanone
(3j). Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (119
1
mg, 68%); mp 67−68 °C; H NMR (400 MHz, CDCl3) δ 2.62 (s,
3H), 7.35 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 8.0
Hz, 1H), 7.59−7.64 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6
Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H); 13C NMR (150 MHz,
CDCl3) δ 23.8, 117.0, 123.2, 125.7, 128.8, 130.0, 130.3, 130.4, 132.4,
132.6, 133.7, 137.2, 137.4, 140.7, 156.4, 157.1, 197.0; HRMS calcd for
C19H15BrNO 352.0332 [M + H]+, found 352.0345.
1-[6-(4-Fluorophenyl)-2-methylpyridin-3-yl]ethanone (3s). Elu-
ent: petroleum ether/ethyl acetate (20:1); yellow solid (79 mg,
69%); mp 69−70 °C (lit.6c 71.3−72.5 °C); 1H NMR (400 MHz,
CDCl3) δ 2.54 (s, 3H), 2.77 (s, 3H), 7.09 (t, J = 8.4 Hz, 2H), 7.52 (d,
J = 8.0 Hz, 1H), 7.96−8.01 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
25.3, 29.3, 115.8 (2JC−F = 21.9 Hz), 116.8, 129.2 (3JC−F = 8.7 Hz),
130.6, 134.5 (4JC−F = 3.6 Hz), 138.1, 157.5, 158.6, 164.0 (1JC−F = 248.0
Hz), 199.8; 19F NMR (376 MHz, CDCl3) δ −111.68; MS m/z 230 [M
+ H]+.
[6-(Benzo[d][1,3]dioxol-5-yl)-2-methylpyridin-3-yl](phenyl)-
methanone (3k). Eluent: petroleum ether/ethyl acetate (20:1); yellow
solid (125 mg, 79%); mp 136−137 °C; 1H NMR (400 MHz, CDCl3)
δ 2.61 (s, 3H), 6.02 (s, 2H), 6.91 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.6
Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.57−7.63 (m, 3H), 7.67 (d, J = 8.0
Hz, 1H), 7.81 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
23.9, 101.4, 107.6, 108.5, 116.2, 121.5, 128.7, 130.0, 131.5, 133.1,
133.5, 137.5, 148.4, 149.0, 157.0, 157.5, 197.2; HRMS calcd for
C20H16NO3 318.1125 [M + H]+, found 318.1132.
2-Phenyl-7,8-dihydroquinolin-5(6H)-one (3t). Eluent: petroleum
ether/ethyl acetate (20:1); white solid (74 mg, 66%); mp 126−127 °C
(lit.6a 128.5−130 °C); 1H NMR (400 MHz, CDCl3) δ 2.18−2.25 (m,
2H), 2.71 (t, J = 7.2 Hz, 2H), 3.21 (t, J = 6.4 Hz, 2H), 7.43−7.51 (m,
3H), 7.69 (d, J = 8.4 Hz, 1H), 8.04−8.06 (m, 2H), 8.31 (d, J = 8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 32.9, 38.6, 118.9, 126.6,
127.5, 128.9, 130.0, 135.8, 138.5, 160.8, 163.8, 197.9; MS m/z 224 [M
+ H]+.
[2-Methyl-6-(thiophen-2-yl)pyridin-3-yl](phenyl)methanone (3l).
Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (114 mg,
1
82%); mp 57−58 °C; H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H),
7.11 (t, J = 4.4 Hz, 1H), 7.41−7.52 (m, 4H), 7.57−7.64 (m, 3H), 7.78
(d, J = 7.6 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 23.7, 115.1,
125.7, 128.3, 128.71, 128.73, 130.0, 131.6, 133.5, 137.48, 137.52,
144.3, 153.2, 157.4, 196.8; HRMS calcd for C17H14NOS 280.0791 [M
+ H]+, found 280.0793.
Ethyl 2,6-Diphenylnicotinate (5a).6b Eluent: petroleum ether/ethyl
1
(6-Cyclohexyl-2-methylpyridin-3-yl)(phenyl)methanone (3m).
acetate (20:1); colorless oil (115 mg, 76%); H NMR (600 MHz,
Eluent: petroleum ether/ethyl acetate (20:1); yellow solid (64 mg,
CDCl3) δ 1.05 (t, J = 7.2 Hz, 3H), 4.16 (q, J = 7.2 Hz, 2H), 7.41−7.46
(m, 6H), 7.64 (d, J = 6.6 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 8.10−8.15
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 13.7, 61.4, 117.9, 125.4,
127.4, 128.1, 128.7, 128.85, 128.94, 129.8, 138.4, 139.0, 140.7, 158.5,
158.8, 168.3; MS m/z 304 [M + H]+.
1
46%); mp 50−51 °C; H NMR (400 MHz, CDCl3) δ 1.27−1.35 (m,
1H), 1.39−1.57 (m, 4H), 1.77 (d, J = 12.8 Hz, 1H), 1.87 (d, J = 12.4
Hz, 2H), 2.00 (d, J = 12.4 Hz, 2H), 2.54 (s, 3H), 2.72−2.79 (m, 1H),
7.06 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.56−7.61 (m, 2H),
7.79 (d, J = 7.6 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 23.6, 26.0,
26.5, 32.9, 46.7, 117.0, 128.6, 130.0, 131.2, 133.4, 137.0, 137.5, 156.1,
168.0, 197.4; HRMS calcd for C19H22NO 280.1696 [M + H]+, found
280.1696.
Ethyl 2-Phenyl-6-(p-tolyl)nicotinate (5b). Eluent: petroleum ether/
1
ethyl acetate (20:1); white solid (124 mg, 78%); mp 63−64 °C; H
NMR (600 MHz, CDCl3) δ 1.05 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 4.15
(q, J = 7.2 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 7.2 Hz, 3H),
7.63 (d, J = 6.6 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.8 Hz,
2H), 8.12 (d, J = 7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 13.8,
21.5, 61.4, 117.6, 125.1, 127.3, 128.1, 128.6, 129.0, 129.6, 135.6, 138.9,
140.0, 140.8, 158.5, 158.8, 168.4; HRMS calcd for C21H20NO2
318.1489 [M + H]+, found 318.1474.
(6-Isopropyl-2-methylpyridin-3-yl)(phenyl)methanone (3n). Elu-
ent: petroleum ether/ethyl acetate (20:1); yellow liquid (53 mg, 44%);
1H NMR (400 MHz, CDCl3) δ 1.34 (d, J = 6.8 Hz, 6H), 2.54 (s, 3H),
3.07−3.14 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H),
7.57−7.62 (m, 2H), 7.79 (d, J = 7.6 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 22.5, 23.6, 36.6, 116.7, 128.6, 130.0, 131.2, 133.4, 137.0,
137.5, 156.2, 168.9, 197.4; HRMS calcd for C16H18NO 240.1383 [M +
H]+, found 240.1389.
Ethyl 2-Phenyl-6-[4-(trifluoromethyl)phenyl]nicotinate (5c). Elu-
ent: petroleum ether/ethyl acetate (20:1); yellow solid (135 mg,
73%); mp 60−61 °C; 1H NMR (600 MHz, CDCl3) δ 1.07 (t, J = 7.2
E
DOI: 10.1021/acs.joc.7b01901
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 3H), 4.18 (q, J = 7.2 Hz, 2H), 7.44 (d, J = 5.4 Hz, 3H), 7.63 (d, J
= 6.0 Hz, 2H), 7.70 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H),
8.16−8.21 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 13.7, 61.6, 118.2,
124.2 (1JC−F = 270.2 Hz), 125.7 (3JC−F = 4.4 Hz), 126.4, 127.7, 128.1,
128.9, 131.4 (2JC−F = 31.7 Hz), 139.1, 140.2, 141.6, 156.7, 158.9,
168.1; 19F NMR (376 MHz, CDCl3) δ −62.68; HRMS calcd for
C21H17F3NO2 372.1206 [M + H]+, found 372.1221.
(d, J = 8.4 Hz, 1H), 8.10 (d, J = 6.8 Hz, 2H), 8.18 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 13.8, 61.5, 118.1, 125.1, 127.3, 128.2,
128.9, 130.0, 130.3, 134.8, 138.1, 139.1, 139.2, 157.7, 158.6, 167.8;
HRMS calcd for C20H16ClNNaO2 360.0762 [M + Na]+, found
360.0761.
Ethyl 2-(4-Fluorophenyl)-6-phenylnicotinate (5l). Eluent: petro-
leum ether/ethyl acetate (20:1); white solid (112 mg, 70%); mp 67−
1
Ethyl 6-(3-Methoxyphenyl)-2-phenylnicotinate (5d). Eluent:
68 °C; H NMR (400 MHz, CDCl3) δ 1.10 (t, J = 7.2 Hz, 3H), 4.18
1
petroleum ether/ethyl acetate (20:1); pink oil (128 mg, 77%); H
(q, J = 7.2 Hz, 2H), 7.12 (t, J = 8.4 Hz, 2H), 7.40−7.45 (m, 3H),
7.60−7.63 (m, 2H), 7.70 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 6.8 Hz, 2H),
8.13 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 61.6,
115.1 (2JC−F = 21.1 Hz), 118.1, 125.2, 127.5, 129.0, 130.0, 130.9 (3JC−F
= 8.8 Hz), 136.8 (4JC−F = 2.9 Hz), 138.3, 139.3, 157.8, 158.6, 163.3
(1JC−F = 246.6 Hz), 168.1; 19F NMR (376 MHz, CDCl3) δ −113.33;
HRMS calcd for C20H16FNNaO2 344.1057 [M + Na]+, found
344.1070.
NMR (600 MHz, CDCl3) δ 1.06 (t, J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.16
(q, J = 7.2 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H),
7.42−7.44 (m, 3H), 7.63−7.66 (m, 3H), 7.71−7.73 (m, 2H), 8.14 (d, J
= 7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 13.7, 55.4, 61.4, 112.9,
115.5, 118.0, 119.8, 125.6, 128.0, 128.6, 128.9, 129.8, 138.9, 139.8,
140.6, 158.2, 158.7, 160.1, 168.3; HRMS calcd for C21H19NNaO3
356.1257 [M + Na]+, found 356.1256.
Ethyl 6-Phenyl-2-(thiophen-2-yl)nicotinate (5m).6b Eluent: petro-
leum ether/ethyl acetate (20:1); colorless oil (94 mg, 61%); 1H NMR
(400 MHz, CDCl3) δ 1.30 (t, J = 7.2 Hz, 3H), 4.36 (q, J = 7.2 Hz,
2H), 7.08 (t, J = 4.8 Hz, 1H), 7.44−7.50 (m, 5H), 7.65 (d, J = 8.0 Hz,
1H), 7.99 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 14.0, 61.8, 117.3, 124.0, 127.2, 127.6, 127.9,
128.6, 128.9, 129.9, 137.9, 138.6, 143.5, 150.5, 157.9, 168.4; HRMS
calcd for C18H16NO2S 310.0896 [M + H]+, found 310.0896.
Ethyl 2-Methyl-6-phenylnicotinate (5n).8c Eluent: petroleum
ether/ethyl acetate (20:1); colorless oil (69 mg, 57%); 1H NMR
(400 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 2.92 (s, 3H), 4.40 (q, J
= 7.2 Hz, 2H), 7.44−7.50 (m, 3H), 7.62 (d, J = 8.0 Hz, 1H), 8.06 (d, J
= 7.2 Hz, 2H), 8.26 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.3, 25.3, 61.1, 117.4, 123.7, 127.3, 128.8, 129.7, 138.6, 139.3, 159.1,
160.0, 166.7; MS m/z 242 [M + H]+.
Ethyl 2-Phenyl-6-(thiophen-2-yl)nicotinate (5e). Eluent: petrole-
um ether/ethyl acetate (20:1); light pink solid (111 mg, 72%); mp
1
46−47 °C; H NMR (600 MHz, CDCl3) δ 1.05 (t, J = 7.2 Hz, 3H),
4.15 (q, J = 7.2 Hz, 2H), 7.10 (s, 1H), 7.42 (s, 1H), 7.60−7.62 (m,
3H), 7.68 (s, 1H), 8.08 (d, J = 7.2 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 13.7, 61.4, 116.2, 124.9, 126.1, 128.0, 128.2, 128.7, 128.9,
129.1, 138.9, 140.1, 144.1, 153.8, 158.9, 168.1; HRMS calcd for
C18H15NNaO2S 332.0716 [M + Na]+, found 332.0716.
Ethyl 6-Cyclohexyl-2-phenylnicotinate (5f). Eluent: petroleum
1
ether/ethyl acetate (20:1); yellow oil (82 mg, 53%); H NMR (400
MHz, CDCl3) δ 0.95 (t, J = 7.2 Hz, 3H), 1.18−1.25 (m, 1H), 1.29−
1.39 (m, 1H), 1.47 (qd, J1 = 12.4 Hz, J2 = 2.8 Hz, 2H), 1.67 (d, J =
12.8 Hz, 1H), 1.78 (d, J = 12.8 Hz, 2H), 1.92 (d, J = 12.0 Hz, 2H),
2.75 (tt, J1 = 11.6 Hz, J2 = 3.6 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 7.10
(d, J = 8.0 Hz, 1H), 7.31−7.35 (m, 3H), 7.45−7.47 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 13.7, 26.0, 26.4, 32.7, 46.6, 61.2, 118.6,
124.6, 128.0, 128.4, 128.7, 138.3, 140.8, 158.2, 168.5, 168.7; HRMS
calcd for C20H24NO2 310.1802 [M + H]+, found 310.1804.
Ethyl 2-Ethyl-6-phenylnicotinate (5o). Eluent: petroleum ether/
1
ethyl acetate (20:1); white solid (70 mg, 55%); mp 57−58 °C; H
NMR (400 MHz, CDCl3) δ 1.36−1.43 (m, 6H), 3.26 (q, J = 7.6 Hz,
2H), 4.39 (q, J = 7.6 Hz, 2H), 7.41−7.50 (m, 3H), 7.61 (d, J = 8.4 Hz,
1H), 8.09 (d, J = 6.8 Hz, 2H), 8.21 (d, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.8, 14.3, 30.5, 61.2, 117.0, 123.4, 127.3, 128.8,
129.6, 138.7, 139.3, 158.9, 164.4, 166.8; HRMS calcd for C16H18NO2
256.1332 [M + H]+, found 256.1352.
Ethyl 6-Isopropyl-2-phenylnicotinate (5g).8i Eluent: petroleum
1
ether/ethyl acetate (20:1); yellow oil (77 mg, 57%); H NMR (400
MHz, CDCl3) δ 1.03 (td, J1 = 7.2 Hz, J2 = 2.8 Hz, 3H), 1.34 (dd, J1 =
6.4 Hz, J2 = 2.8 Hz, 6H), 3.13−3.21 (m, 1H), 4.13 (qd, J1 = 7.2 Hz, J2
= 2.8 Hz, 2H), 7.21 (dd, J1 = 8.0 Hz, J2 = 2.8 Hz, 1H), 7.41−7.42 (m,
3H), 7.54−7.56 (m, 2H), 8.03 (dd, J1 = 8.0 Hz, J2 = 2.4 Hz, 1H); 13
C
Methyl 2-Ethyl-6-phenylnicotinate (5p). Eluent: petroleum ether/
1
NMR (100 MHz, CDCl3) δ 13.6, 22.4, 36.5, 61.2, 118.2, 124.7, 128.0,
128.4, 128.8, 138.3, 140.7, 158.1, 168.5, 169.5; MS m/z 270 [M + H]+.
Ethyl 2,4-dDiphenylnicotinate (5h).6e Eluent: petroleum ether/
ethyl acetate (20:1); white solid (72 mg, 60%); mp 54−55 °C; H
NMR (400 MHz, CDCl3) δ 1.38 (t, J = 7.6 Hz, 3H), 3.26 (q, J = 7.6
Hz, 2H), 3.88 (s, 3H), 7.38−7.46 (m, 3H), 7.55 (d, J = 8.4 Hz, 2H),
8.07 (d, J = 7.2 Hz, 2H), 8.16 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 13.7, 30.4, 52.1, 117.0, 123.0, 127.3, 128.8, 130.0,
138.6, 139.4, 158.9, 164.5, 167.1; HRMS calcd for C15H16NO2
242.1176 [M + H]+, found 242.1196.
1
ethyl acetate (20:1); yellow oil (48 mg, 32%); H NMR (400 MHz,
CDCl3) δ 0.86 (t, J = 7.2 Hz, 3H), 3.95 (q, J = 7.6 Hz, 2H), 7.29 (d, J
= 4.8 Hz, 2H), 7.42 (s, 8H), 7.63 (d, J = 6.8 Hz, 2H), 8.74 (d, J = 5.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.4, 61.4, 122.8, 128.1,
128.3, 128.4, 128.6, 128.7, 128.8, 138.1, 139.7, 148.6, 149.8, 156.9,
168.4; MS m/z 304 [M + H]+.
Procedures for the Synthesis of 6 and 7 and Spectroscopic Data
of 6 and 7. To a solution of (2,6-diphenylpyridin-3-yl)(phenyl)-
methanone (3p, 167.5 mg, 0.5 mmol) in methanol (3 mL) was slowly
added NaBH4 (18.9 mg, 0.5 mmol). The resulting mixture was stirred
at room temperature. Upon completion as indicated by TLC, the
reaction was quenched with water and the mixture was extracted with
ethyl acetate (3 × 8 mL). The combined organic layers were washed
with brine (5 mL), dried over anhydrous Na2SO4, and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel with a petroleum ether/ethyl acetate
(10:1) eluent to give 6.
(2,6-Diphenylpyridin-3-yl)(phenyl)methanol (6). Eluent: petrole-
um ether/ethyl acetate (10:1); yellowish solid (153 mg, 91%); mp
148−149 °C; 1H NMR (400 MHz, CDCl3) δ 2.43 (d, J = 4.0 Hz, 1H),
5.98 (d, J = 2.8 Hz, 1H), 7.14−7.16 (m, 2H), 7.21−7.34 (m, 3H),
7.36−7.43 (m, 6H), 7.47−7.49 (m, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.90
(d, J = 8.0 Hz, 1H), 8.00−8.02 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 71.9, 119.4, 126.7, 127.1, 127.6, 128.2, 128.3, 128.5, 128.7,
129.0, 129.3, 135.1, 136.8, 139.1, 140.0, 143.2, 156.0, 157.8; HRMS
calcd for C24H20NO 338.1539 [M + H]+, found 338.1540.
Ethyl 6-Phenyl-2-(p-tolyl)nicotinate (5i). Eluent: petroleum ether/
1
ethyl acetate (20:1); yellow solid (116 mg, 73%); mp 46−47 °C; H
NMR (400 MHz, CDCl3) δ 1.12 (t, J = 7.2 Hz, 3H), 2.41 (s, 3H), 4.20
(q, J = 7.2 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.41−7.49 (m, 3H), 7.55
(d, J = 7.6 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 13.8, 21.4, 61.4, 117.6, 125.2, 127.3,
128.7, 128.78, 128.83, 129.7, 137.7, 138.4, 138.6, 138.8, 158.4, 158.7,
168.4; HRMS calcd for C21H20NO2 318.1489 [M + H]+, found
318.1489.
Ethyl 2-(4-Methoxyphenyl)-6-phenylnicotinate (5j).6b Eluent:
1
petroleum ether/ethyl acetate (20:1); yellow oil (135 mg, 81%); H
NMR (400 MHz, CDCl3) δ 1.18 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.19
(q, J = 7.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 7.38−7.45 (m, 3H),
7.61−7.66 (m, 3H), 8.09 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 55.4, 61.4, 113.6, 117.3, 125.0, 127.3, 128.8, 129.7,
130.4, 133.0, 138.4, 138.9, 158.1, 158.2, 160.3, 168.6; HRMS calcd for
C21H19NNaO3 356.1257 [M + Na]+, found 356.1259.
Ethyl 2-(4-Chlorophenyl)-6-phenylnicotinate (5k). Eluent: petro-
leum ether/ethyl acetate (20:1); white solid (121 mg, 72%); mp 68−
To a flask containing (2,6-diphenylpyridin-3-yl)(phenyl)methanol
(6, 67.4 mg, 0.2 mmol) in CH2Cl2 (2 mL) was added TfOH (35 μL,
0.4 mmol). Then, the mixture was stirred at room temperature. Upon
1
69 °C; H NMR (400 MHz, CDCl3) δ 1.13 (t, J = 7.2 Hz, 3H), 4.20
(q, J = 7.2 Hz, 2H), 7.41−7.49 (m, 5H), 7.58 (d, J = 8.4 Hz, 2H), 7.76
F
DOI: 10.1021/acs.joc.7b01901
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
completion, the reaction was quenched with aqueous NaHCO3 (5
mL) and the mixture was extracted with ethyl acetate (3 × 6 mL). The
combined organic layers were washed with water and brine and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum, and the crude product was purified by column chromatog-
raphy on silica gel with a petroleum ether/ethyl acetate (10:1) eluent
to afford 7.
*E-mail: xinyingzhang@htu.cn.
ORCID
Xinying Zhang: 0000-0002-3416-4623
Xuesen Fan: 0000-0002-2040-6919
Notes
The authors declare no competing financial interest.
2,5-Diphenyl-5H-indeno[1,2-b]pyridine (7). Eluent: petroleum
ether/ethyl acetate (10:1); white solid (46 mg, 72%); mp 144−145
°C; 1H NMR (400 MHz, CDCl3) δ 5.08 (s, 1H), 7.11−7.13 (m, 2H),
7.26−7.32 (m, 3H), 7.37−7.45 (m, 3H), 7.47−7.52 (m, 3H), 7.59 (d, J
= 8.0 Hz, 1H), 7.64 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 8.12−8.14 (m,
2H), 8.23 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 52.0,
118.8, 121.2, 125.3, 127.1, 127.2, 127.8, 128.3, 128.75, 128.81, 128.9,
129.3, 133.1, 139.8, 140.0, 140.49, 140.51, 148.7, 156.9, 160.1; HRMS
calcd for C24H18N 320.1434 [M + H]+, found 320.1441.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (NSFC) (Grant 21572047), the Program for Innovative
Research Team in Science and Technology in Universities of
Henan Province (15IRTSTHN003), and the Program for
Science and Technology Innovation Talents in Universities of
Henan Province (15HASTIT005) for financial support.
Typical Procedure for the Synthesis of 8a and Spectroscopic
Data of 8a and 8b. To a flask containing ethyl 2,6-diphenylnicotinate
(5a, 151.5 mg, 0.5 mmol) was added polyphosphoric acid (1 mL). The
mixture was then stirred at 135 °C. Upon completion, it was cooled to
room temperature, treated with a saturated aqueous solution of
NaHCO3 (5 mL), and extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were washed with water and brine, dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel with a
petroleum ether/ethyl acetate (20:1) eluent to give 8a. 8b was
obtained in a similar manner.
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1
°C; H NMR (400 MHz, CDCl3) δ 7.40 (t, J = 7.6 Hz, 1H), 7.46−
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1
°C; H NMR (400 MHz, CDCl3) δ 1.35 (d, J = 6.8 Hz, 6H), 3.08−
3.19 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.56
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Gram-Scale Synthesis of 3a. To a reaction tube equipped with a
stir bar containing a solution of 3-amino-1-phenylbut-2-en-1-one (2a,
805 mg, 5 mmol) in DMF (15 mL) were added propiophenone 1a
(0.80 mL, 6 mmol), Cu(OAc)2 (91 mg, 0.5 mmol), 2,2′-bipyridine
(156 mg, 1 mmol), and TEMPO (781 mg, 5 mmol). The tube was
then sealed, and the mixture was stirred at 120 °C under an air
atmosphere for 20 h. After the mixture had been cooled to room
temperature, the reaction was quenched with water, and the mixture
was extracted with ethyl acetate (3 × 40 mL). The combined organic
layers were washed with water (20 mL) and brine (20 mL), dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel with a
petroleum ether/ethyl acetate (20:1) eluent to give 3a (0.892 g, 65%).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01901.
1
Copies of H and 13C NMR spectra of all products
(PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: xuesen.fan@htu.cn.
■
G
DOI: 10.1021/acs.joc.7b01901
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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DOI: 10.1021/acs.joc.7b01901
J. Org. Chem. XXXX, XXX, XXX−XXX