Copper-catalyzed formal C-N bond cleavage of aromatic methylamines: Assembly of pyridine derivatives

Article abstract of DOI:10.1021/jo400261v

An efficient copper-catalyzed C-N bond cleavage of aromatic methylamines was developed to construct pyridine derivatives. With neat conditions and facile operation, the fragment-assembling strategy affords a broad range of 2,4,6-trisubstituted pyridines in up to 95% yield from simple and readily available starting materials. Interestingly, when pyridin-2-yl methylamine was employed as the substrate, α-alkylation reaction of ketones readily occurred to give β-(pyridin-2-yl) ketones instead of the 2,4,6-trisubstituted pyridines.

Full text of DOI:10.1021/jo400261v

Article
pubs.acs.org/joc
Copper-Catalyzed Formal C−N Bond Cleavage of Aromatic
Methylamines: Assembly of Pyridine Derivatives
Huawen Huang, Xiaochen Ji, Wanqing Wu, Liangbin Huang, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640,
People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient copper-catalyzed C−N bond
cleavage of aromatic methylamines was developed to construct
pyridine derivatives. With neat conditions and facile operation,
the fragment-assembling strategy affords a broad range of
2,4,6-trisubstituted pyridines in up to 95% yield from simple
and readily available starting materials. Interestingly, when
pyridin-2-yl methylamine was employed as the substrate, α-alkylation reaction of ketones readily occurred to give β-(pyridin-2-yl)
ketones instead of the 2,4,6-trisubstituted pyridines.
featured high reactivity in the copper-catalyzed α-alkylation
reaction of ketones to afford pharmacologically significant
β-(pyridin-2-yl) ketones.
INTRODUCTION
■
It is known that pyridine forms the structural core of many
natural products, pharmaceutical agents, and functionalized
materials.1 In particular, β-(pyridin-2-yl) ketones were identified
as lead structures for a series of pyridine derivatives with umami
flavor (UF, Figure 1), which were widely applied as wonderful
Other aromatic methylamines also proceeded C−N bond
cleavage in the copper-catalytic system with ketones. Instead
of generation of β-aryl ketones, both carbon and nitrogen
components of bond-cleavage were trapped by ketones to
assemble 2,4,6-trisubstituted pyridine derivatives. This fragment-
assembling strategy would be of great interest and potential
applications due to the high atom economy, and offer
opportunities to achieve desirable synthetic convergence and
flexibility to improve overall efficiency. With this strategy, for
example, Xi and co-workers reported a novel isomerization for
the synthesis of dihydropyrimidine derivatives by C−N bond
cleavage of azetidines and intramolecular ring-closing reaction.6
Herein, for the first time, we report a copper-catalyzed C−N
bond cleavage of aromatic methylamines with molecular oxygen
as the oxidant for ready generation of 2,4,6-trisubstituted pyridine
derivatives. From simple and readily available starting materials,
the present protocol features advantages including atom economy,
neat conditions (minimized waste), environmentally friendly
oxidant, and nonhazardous byproduct (water), and more
importantly offers great flexibility in the construction of nitrogen-
containing heterocycles under Cu/O2 systems.7
Figure 1. Structure of UF and B3PyPB.
alternatives to monosodium glutamate in the food industry.1e
Compound B3PyPB (Figure 1), one of the pyridine-based
π-conjugated systems, was used in high-performance FIrpic-
based organic light-emitting device (OLED).1d Consequently,
pyridine synthesis remains a topic of considerable interest in
modern synthetic chemistry.2
Synthetic strategies involving C−N bond cleavage have been
widely investigated. Classic examples include deprotection of
N-protecting groups3 and cross-coupling reactions4 by C−N
bond cleavage, both of which are powerful tools having great
significance for synthetic and pharmacological chemistry due to
the efficiency and versatility for rapid generation of a broad range
of functionalized products. Among them, cross-coupling reacions
through C−N bond cleavage of N-benzylic sulfonamides5
provided a convenient access to α-alkylation of ketones,5a,b
Friedel−Crafts alkylation of indoles,5c,d and other C−C bond
forming reactions.5e,f However, the employment of N-protected
benzyl amines in previous work limited the application of this
methodology. In this paper, we found pyridin-2-yl methylamine
RESULTS AND DISCUSSION
■
Synthesis of 2,4,6-Trisubstituted Pyridines. Initially,
1-(p-tolyl)ethanone (1b, 2 mmol) and benzylamine (2a, 1.2
mmol), treated with copper catalyst under air and neat conditions,
were chosen as the model system (Table 1). To our delight, after
heating the mixture at 100 °C for 20 h, this reaction with CuI,
CuBr, or CuCl2 afforded a certain yield of 2,4,6-trisubstituted
pyridine 3ba (entries 1−3) bearing symmetrical structure, which
Received: February 4, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
such as 1e, 1f, and 1g (Table 2, entries 5−7). Morpholino sub-
stituent (1j) and naphthalene (1k), with toluene as the solvent
for convenience of operation, were tolerated to afford moderate
yields of pyridine products. Both thiophen-2-yl and furan-2-yl
methyl ketones 1l,m showed high reactivities (Table 2, entries
12, 13); however, the desired 2,4,6-trisubstituted pyridine
products were obtained with considerably different yields (94%
of 3la and 42% of 3ma, respectively). Then alkyl methyl ketones
were subjected to this reaction to react with 2a. Generally,
2,6-dialkyl-substituted pyridines were obtained in moderate
yields (Table 2, entries 14−19), including alkenyl substituent
tolerated well (entry 19). It should be noted that acetone was
also productive under the standard conditions and gave the
corresponding product in 50% yield (entry 18). Unfortunately,
nonmethyl ketones, such as cyclohexanone, propiophenone, and
3-pentanone, led to the desired pyridines in very low GC yields.
Next, substituted benzyl amines were employed to give the
expected pyridines in excellent yields (80−92%, Table 3, entries
1−5). Heteroaryl methylamines featured considerably different
reactivities. While furan-2-yl, thien-2-yl, and pyridin-3-yl methyl-
amines could efficiently yield pyridines (Table 3, entries 6−8),
2-pyridyl and 4-pyridyl methylamines failed to transfer to the
corresponding products. Furanyl methylamine and thienyl ketone
gave 2,4,6-triheteroaryl pyridine 3lg in good yield (Table 3,
entry 9).
Table 1. Screening the Reaction Conditions
temperature
yield
(%)
entry
[Cu] catalyst
CuI
oxidant
air
solvent
(°C)
1
2
3
4
5
6
7
8
neat
neat
neat
neat
neat
neat
neat
neat
neat
100
100
100
100
100
100
80
32
20
CuBr
air
air
air
CuCl2
29
Cu(OAc)2
trace
60
Cu(OOCCF3)2 air
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
−
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
air
air
air
air
73
68
120
100
100
100
100
100
100
100
100
100
73
b
9
91
c
10
O2 (1 atm) neat
O2 (1 atm) neat
75
d
11
92
e
12
−
neat
trace
trace
77
f
13
O2 (1 atm) neat
O2 (1 atm) water
O2 (1 atm) DMSO
O2 (1 atm) toluene
O2 (1 atm) DMF
g
14
g
15
80
g
16
89
Surprisingly, N-methyl or N-benzyl benzylamines 2j−l were
also successfully subjected to this reaction system and provided
pyridine 3aa in moderate to excellent yields with cleavage of
two or three C−N bonds (Table 4, entries 1−3), although
N-isopropyl benzylamine (2m) failed to react under the optimized
reaction conditions (Table 4, entry 4). Likewise, benzylamine with
α-carboxylic acid or ester substituent could transfer to pyridine
3aa with C−N bond cleavage and decarboxylation (Table 4,
entries 5−6).
g
17
47
a
The reaction was performed in an opened tube (25 mL) with 1b
(2 mmol), 2a (1.2 mmol) and [Cu] catalyst (0.1 mmol) for 20 h. GC
yield based on 1b was given. Using 1.6 mmol of 2a. An O2 balloon
was attached to the tube. The reaction was performed in a sealed tube
(25 mL) filled with O2 (1 atm). Under nitrogen atmosphere. In the
b
c
d
e
f
g
absence of Cu(OTf)2. 0.5 mL of solvent was used.
Two-fold C−N bond cleavage of xylylenediamine (2p)
enabled 2-fold pyridine assembly and readily provided bis-
(pyridin-4-yl)benzene 3ap in good yield [eq 1]. Such multifold
cyclizations may serve as an attractive route to extended
π-conjugated systems for potential applications in OLED.1c,d
indicated a C−N bond cleavage of 2a/condensation/oxidation
reaction sequence in this transformation. Among the copper
catalysts screened (entries 3−6), Cu(OTf)2 (5 mol %) was found
to be the best catalyst to give the target 3ba in 73% yield (entry 6),
in which benzylamine was converted completely with some
ketone 1b left. Screening different reaction temperature suggested
100 °C was optimal (entries 7−8). Compared with air, the reaction
equipped with an O2 (1 atm) balloon gave a slight increase in the
yield (entry 10). Gratifyingly, the reaction performed in a sealed
tube filled with oxygen atmosphere (1 atm) increased the yield to
92% (entry 11), while with an opened system under air, more than
1.6 equiv (1.6 mmol) of benzylamine were required to facilitate
a full conversion of ketone (entry 9). Furthermore, this reaction
could not yield the target product under nitrogen atmosphere
(entry 12) or without additional copper catalyst (entry 13). The
employment of solvent in this system just decreased the yield of
3ba (entries 14−17), whereas toluene had no obvious influence on
the transformation (entry 16). Thus, the optimal reaction condi-
tion is ketone (2 mmol, 1 equiv), benzylamine (0.6 equiv), and
Cu(OTf)2 (5 mol %) conducted in a sealed tube filled with oxygen
atmosphere (1 atm) at 100 °C for 20 h.
In this copper/oxygen catalytic system, cross reactions with
two different methyl ketones provided asymmetrically sub-
stituted pyridines as major products. As shown in Scheme 1,
1-(4-methoxyphenyl)ethanone (1e, 1 mmol) and benzylamine
(2a, 1.2 mmol), when treated with methyl ketone (1 mmol), such
as 1a, 1c, 1l, and 1o, smoothly afforded pyridines 4a, 4b, 4c, and
4d, respectively, in moderate yields.
To shed light on the reaction mechanism, several controlled
experiments were conducted. Aerobic oxidation of benzylamine
to imine 5 efficiently occurred under this Cu/O2 system [eq 2].
When treated with 4-methylbenzaldehyde (1 equiv), ketone 1a
and benzylamine 2a (1 equiv) afforded 4-(p-tolyl)-pyridine 3ak
as the main product [eq 3], which indicated that the aldehyde
was probably the key intermediate in this chemical process.
With the experimental results obtained, a circular reaction path-
way is proposed as shown in Scheme 2. First, Cu(II)-mediated
single-electron oxidation7d of benzylamine and aminolysis
With the optimized reaction conditions in hand, we employed
various methyl ketones with benzylamine to explore the
generality of the pyridine assembly under the Cu/O2 system
(Table 2). Phenyl methyl ketones with electron-donating or
electron-withdrawing substituents on the aromatic ring reacted
well to give the corresponding products (Table 2, entries 1−10).
Slight steric effect was observed when the substituents were pre-
sented on the para, meta, and ortho positions of the benzene ring,
B
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Synthesis of 2,4,6-Trisubstituted Pyridines via C−N Bond Cleavage
a
b
Reagents and conditions: 1 (2 mmol), 2 (1.2 mmol), and Cu(OTf)2 (0.1 mmol) at 100 °C for 20 h. Isolated yields were given. Using toluene
c
(0.5 mL) as the solvent. At 80 °C for 8 h.
provided imine 5.8 Then hydrolysis of imine would give
benzaldehyde and benzylamine, which is a reversible process
(Scheme 2, path A). Subsequently, promoted by Lewis acidic
Cu(II), the condensation9 of ketone, benzylamine, and benzal-
dehyde afforded intermediate 1,4-dihydropyridine intermediate
II. Finally, II was readily oxidized to the final product 3aa and
generated benzaldehyde via oxidative hydrolysis under Cu/O2
catalytic system. The benzaldehyde would participate in the
next pyridine formation (Scheme 2, path B). Additionally,
either imine 5 replacing benzaldehyde or ammonia replacing
benzylamine could serve as corresponding component in the
condensation process.
C
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 3. Synthesis of 2,4,6-Trisubstituted Pyridines via C−N
Table 4. Pyridine Synthesis via Cleavage of C−C and C−N
a
a
Bond Cleavage
Bonds
entry
2 (R/R1/R2)
yield (%)
1
2
3
4
5
6
2j (H/H/Me)
78
54
2k (H/Me/Me)
2l (H/H/Bn)
90
2m (H/H/i-Pr)
2n (COOH/H/H)
2o (COOMe/H/H)
trace
80
55
a
Reagents and conditions: 1a (2 mmol), 2 (1.2 mmol), and Cu(OTf)2
(0.1 mmol) at 100 °C for 20 h.
Scheme 1. Synthesis of Asymmetrical Pyridines
deamination cross-coupling reaction [eq 4]. To the best of our
knowledge, this is the first exmple of α-alkylation reaction of
Scheme 2. Plausible Reaction Mechanism for the Synthesis of
2,4,6-Trisubstituted Pyridines
a
Reagents and conditions: 1 (2 mmol), 2 (1.2 mmol), and Cu(OTf)2
(0.1 mmol) at 100 °C for 20 h.
Synthesis of β-(Pyridin-2-yl)-ketones. As described above,
under the copper-catalyzed system, 2-pyridyl methylamine 2j
with ketone 1a could not generate 2,4,6-trisubstituted pyridine.
Instead, the chain product 3j−a was obtained in 72% yield via
D
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ketones using primary monoaryl methylamine as the reaction
partner. After simple optimization of the reaction conditions,
this reaction could afford 3j−a in 95% yield at 80 °C for 12 h
(Scheme 3). Other ketones such as substituted phenyl ketones,
intermediate C, formed via coordination interaction between
A and B, underwent intramolecular nucleophilic attack and
Scheme 3. Scope of the Deamination Cross-Coupling
Reaction
Scheme 4. Plausible Reaction Mechanism for the Cross-
Coupling Reaction
naphthyl ketone, thienyl ketone, and pyridyl ketone could be
also converted to the corresponding chain products in good
yields with C(sp3)−C(sp3) bond formation. It is surprising that
nonmethyl ketones, such as cyclohexanone, propiophenone, and
3-pentanone, also featured high activities in this reaction system,
giving the corresponding β-(pyridin-2-yl)-ketones in good to
excellent yields.
carbon−nitrogen bond cleavage in an SN2 manner to provide the
final product 3j−a.
N-Methyl-1-(pyridin-2-yl)methanamine (2k) also smoothly
reacted with ketone 1a under this reaction system, affording the
desired product 3j−a in 77% yield [eq 5]. However, N-tosyl-1-
(pyridin-2-yl)methanamine (2l) failed to give the final pyridine
[eq 6], probably because the protonation of the tosyl-protected
amine did not easily occur. Finally, it was found that pyridin-2-
ylmethanol (2m) was unable to yield the corresponding product,
which suggested that 2m was not the intermediate product in this
transformation.
Interestingly, this cross-coupling reaction occurred only in the
case of 2-pyridyl methylamine, which suggested the coordination
interaction between copper catalyst and 2-pyridyl methylamine
would play a key role in the transformation. A plausible reaction
mechanism is proposed as shown in Scheme 4. Interaction of
Cu(OTf)2 and ketone 1a afforded alkenyloxy copper species A,
and simultaneously generated HOTf, which would react with
2-pyridyl methylamine (2j) to give ammonium B. Subsequently,
CONCLUSIONS
■
In summary, a practical copper-catalyzed C−N bond cleavage of
aromatic methylamines was developed to construct function-
alized pyridine derivatives. A series of 2,4,6-trisubstituted
pyridines was efficiently obtained in moderate to excellent
yields. This process should be initiated by copper-catalyzed
aerobic oxidative cleavage of C−N bond of aromatic methyl-
amines. A wide range of ketones and aromatic methylamines
were tolerated well in this Cu/O2 catalytic system. This
fragment-assembling strategy is highly compatible with the
goal of sustainable and green chemistry. In particular, pyridin-2-
yl methylamine could transfer to different β-(pyridin-2-yl)
ketones in good yields via α-alkylation of ketones. The finding
that different aromatic methylamines show different reaction
selectivity under copper catalysis system might open up a new
way to design functionalized molecules in organic synthesis.
E
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(d, J = 8.7 Hz, 4H), 7.86 (s, 2H), 7.73 (d, J = 6.9 Hz, 2H), 7.59−7.48 (m,
3H), 7.37 (d, J = 8.3 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 156.2,
150.6, 150.0, 138.6, 137.9, 129.3, 129.2, 128.6, 127.1, 121.0, 120.5,
117.2; HRMS (ESI) calc. C25H15F6NO2 [M + H]+ 476.1080, found
476.1103.
2,6-Bis(4-(methylthio)phenyl)-4-phenylpyridine (3ia). In 85%
yield (339 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J =
8.4 Hz, 4H), 7.83 (s, 2H), 7.73 (d, J = 7.1 Hz, 2H), 7.58−7.47 (m, 3H),
7.38 (d, J = 8.4 Hz, 4H), 2.55 (s, 6H); 13C NMR (101 MHz, CDCl3)
δ 156.8, 150.2, 139.9, 139.0, 136.2, 129.1, 128.9, 127.4, 127.1, 126.4,
116.5, 15.6; HRMS (ESI) calc. C25H21NS2 [M + H]+ 400.1188, found
400.1192.
EXPERIMENTAL SECTION
■
General Methods. 1H and 13C NMR spectra were recorded using
a 400 MHz NMR spectrometer. The chemical shifts were referenced
to signals at 7.26 and 77.0 ppm, respectively, and CDCl3 was used as
the solvent with TMS as the internal standard. High-resolution mass
spectra were obtained with a LCMS-IT-TOF mass spectrometer. TLC
was performed by using commercially prepared 100−400 mesh silica
gel plates (GF254), and visualization was effected at 254 nm. Unless
otherwise noted, all commercial materials and solvents were used
without further purification.
General Procedure for the Synthesis of 2,4,6-Trisubstituted
Pyridines. To a 25 mL pressure tube was added a mixture of ketone
1 (2 mmol), benzylamine 2 (1.2 mmol), and Cu(OTf)2 (36 mg, 0.1 mmol),
successively. Subsequently, the tube was evacuated with a vacuum pump,
filled with oxygen (1 atm), and sealed with Teflon stopper. The mixture
was stirred at 100 °C for 20 h. Upon completion, the crude product was
cooled to room temperature and then directly separated by flash column
chromatography on silica gel to give the pure product 3. Pyridines 3ja
and 3ka were prepared using toluene (0.5 mL) as the solvent for
convenience of stirring. Pyridines 3la and 3ma were obtained at 80 °C
for 8 h. Asymmetrical pyridines 4a−d were synthesized according to this
procedure using two different ketones (1 mmol for each).
4,4′-((4-Phenylpyridine-2,6-diyl)bis(4,1-phenylene))-
1
dimorpholine (3ja). In 54% yield (258 mg), white solid: H NMR
(400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 4H), 7.75 (d, J = 10.0 Hz, 4H),
7.55−7.45 (m, 3H), 7.02 (d, J = 8.8 Hz, 4H), 3.88 (t, J = 4.8 Hz, 8H),
3.25 (t, J = 4.8 Hz, 8H); 13C NMR (101 MHz, CDCl3) δ 156.9, 151.7,
149.7, 139.4, 131.0, 128.9, 128.7, 127.9, 127.1, 115.1, 115.1, 66.7, 48.7;
HRMS (ESI) calc. C31H31N3O2 [M + H]+ 478.2489, found 478.2497.
2,6-Di(naphthalen-2-yl)-4-phenylpyridine (3ka).9b In 48%
1
yield (195 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.71 (s,
2H), 8.45 (dd, J = 8.6, 1.2 Hz, 2H), 8.06−8.01 (m, 6H), 7.96−7.90 (m,
2H), 7.83 (d, J = 7.3 Hz, 2H), 7.62−7.50 (m, 7H); 13C NMR (101 MHz,
CDCl3) δ 157.4, 150.2, 139.0, 136.9, 133.7, 133.5, 129.1, 129.0, 128.7,
128.4, 127.7, 127.2, 126.5, 126.4, 126.2, 124.9, 117.4; HRMS (ESI) calc.
C31H21N [M + H]+ 408.1747, found 408.1750.
2,4,6-Triphenylpyridine (3aa).10 In 91% yield (279 mg), white
1
solid: H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.1 Hz, 4H), 7.91
(s, 2H), 7.77 (d, J = 7.0 Hz, 2H), 7.57−7.43 (m, 9H); 13C NMR
(101 MHz, CDCl3) δ 157.5, 150.3, 139.5, 139.0, 129.1, 129.1, 129.0,
128.7, 127.2, 127.2, 117.2; HRMS (ESI) calc. C23H17N [M + H]+
308.1434, found 308.1442.
4-Phenyl-2,6-di(thiophen-2-yl)pyridine (3la).11 In 94% yield
(300 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 7.70−7.56 (m,
6H), 7.50−7.33 (m, 5H), 7.08 (t, J = 4.1 Hz, 2H); 13C NMR (101 MHz,
CDCl3) δ 152.5, 145.0, 144.8, 138.4, 129.0, 129.0, 127.9, 127.7, 126.9,
124.7, 114.9; HRMS (ESI) calc. C19H13NS2 [M + H]+ 320.0562, found
320.0570.
4-Phenyl-2,6-di-p-tolylpyridine (3ba).9b In 90% yield (301 mg),
white solid: 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.9 Hz, 4H), 7.79
(s, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.49−7.38 (m, 3H), 7.28 (d, J = 7.9 Hz,
4H), 2.39 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 157.3, 149.9, 139.2,
138.9, 136.8, 129.3, 129.0, 128.8, 127.1, 126.9, 116.4, 21.3; HRMS (ESI)
calc. C25H21N [M + H]+ 336.1747, found 336.1750.
2,6-Di(furan-2-yl)-4-phenylpyridine (3ma).12 In 42% yield
1
(121 mg), white solid: H NMR (400 MHz, CDCl3) δ 7.81 (s, 2H),
7.76 (d, J = 7.0 Hz, 2H), 7.60−7.44 (m, 5H), 7.23 (d, J = 3.2 Hz, 2H),
6.57 (dd, J = 3.3, 1.7 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 153.7,
149.9, 149.6, 143.3, 138.3, 129.2, 129.0, 127.0, 114.8, 112.1, 109.3;
HRMS (ESI) calc. C19H13NO2 [M + H]+ 288.1019, found 288.1031.
2,6-Diphenethyl-4-phenylpyridine (3na). In 61% yield
2,6-Bis(4-fluorophenyl)-4-phenylpyridine (3ca).9b In 91% yield
(312 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.2,
5.6 Hz, 4H), 7.82 (s, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.58−7.46 (m, 3H),
7.20 (t, J = 8.5 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 163.6, 156.4,
150.4, 138.8, 135.5, 129.1, 129.1, 128.9, 127.1, 116.7, 115.5; HRMS
(ESI) calc. C23H15F2N [M + H]+ 344.1245, found 344.1246.
2,6-Bis(4-chlorophenyl)-4-phenylpyridine (3da).9b In 75%
1
(221 mg), yellowish oil: H NMR (400 MHz, CDCl3) δ 7.51−7.38
(m, 5H), 7.30−7.18 (m, 10H), 7.10 (s, 2H), 3.21−3.08 (m, 8H); 13C
NMR (101 MHz, CDCl3) δ 160.8, 149.6, 148.6, 141.4, 138.4, 129.0,
128.6, 128.3, 127.1, 126.0, 118.9, 39.8, 36.1; HRMS (ESI) calc. C27H25N
[M + H]+ 364.2060, found 364.2068.
1
yield (281 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.13 (d,
J = 7.9 Hz, 4H), 7.85 (s, 2H), 7.72 (d, J = 7.7 Hz, 2H), 7.57−7.46 (m,
7H); 13C NMR (101 MHz, CDCl3) δ 156.3, 150.6, 138.6, 137.7, 135.3,
129.2, 129.1, 128.9, 128.3, 127.1, 117.1; HRMS (ESI) calc. C23H15Cl2N
[M + H]+ 376.0654, found 376.0699.
2,6-Dicyclopropyl-4-phenylpyridine (3oa). In 75% yield
1
(176 mg), yellowish oil: H NMR (400 MHz, CDCl3) δ 7.63 (d, J =
7.8 Hz, 2H), 7.50−7.38 (m, 3H), 7.10 (d, J = 0.4 Hz, 2H), 2.12−1.94 (m,
2H), 1.12−1.03 (m, 4H), 0.97−0.90 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 162.3, 148.1, 139.2, 128.8, 128.4, 127.0, 116.2, 17.1, 9.4;
HRMS (ESI) calc. C17H17N [M + H]+ 236.1434, found 236.1435.
2,6-Diisobutyl-4-phenylpyridine (3pa). In 70% yield (187 mg),
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.73−7.58 (m, 2H), 7.50−
7.34 (m, 3H), 7.15 (s, 2H), 2.72 (d, J = 7.3 Hz, 4H), 2.22−2.10 (m, 2H),
0.97 (d, J = 6.7 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 161.3, 148.2,
138.9, 128.8, 128.5, 126.9, 118.6, 47.6, 29.2, 22.3; HRMS (ESI) calc.
C19H25N [M + H]+ 268.2060, found 268.2065.
2,6-Bis(4-methoxyphenyl)-4-phenylpyridine (3ea).9b In 87%
yield (319 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J =
8.7 Hz, 4H), 7.79 (s, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.56−7.45 (m, 3H),
7.06 (d, J = 8.7 Hz, 4H), 3.89 (s, 6H); 13C NMR (101 MHz, CDCl3)
δ 160.5, 156.9, 149.9, 139.3, 132.3, 129.0, 128.8, 128.3, 127.1, 115.6,
114.0, 55.3; HRMS (ESI) calc. C25H21NO2 [M + H]+ 368.1645, found
368.1650.
2,6-Bis(3-methoxyphenyl)-4-phenylpyridine (3fa).9b In 85%
yield (312 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 2H),
7.87 (s, 2H), 7.81−7.75 (m, 4H), 7.57−7.44 (m, 5H), 7.04 (dd, J = 8.1,
2.3 Hz, 2H), 3.95 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 160.0, 157.0,
150.0, 140.9, 138.8, 129.6, 129.0, 128.9, 127.1, 119.4, 117.2, 114.6,
112.6, 55.3; HRMS (ESI) calc. C25H21NO2 [M + H]+ 368.1645, found
368.1654.
2,6-Dipentyl-4-phenylpyridine (3qa). In 55% yield (162 mg),
yellowish oil: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.1 Hz, 2H),
7.48−7.37 (m, 3H), 7.17 (s, 2H), 2.87−2.77 (m, 4H), 1.81−1.70 (m,
4H), 1.43−1.30 (m, 8H), 0.90 (t, J = 7.0 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 162.3, 148.9, 139.0, 128.9, 128.6, 127.0, 117.8, 38.6, 31.7,
29.9, 22.5, 14.0; HRMS (ESI) calc. C21H29N [M + H]+ 296.2373, found
296.2379.
2,6-Bis(2-methoxyphenyl)-4-phenylpyridine (3ga). In 70%
1
yield (257 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.05 (s,
2,6-Dimethyl-4-phenylpyridine (3ra).13 In 50% yield (92 mg),
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 6.9 Hz, 2H),
7.43−7.33 (m, 3H), 7.12 (s, 2H), 2.53 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 158.0, 149.1, 138.6, 128.9, 128.7, 127.0, 118.4, 24.5; HRMS
(ESI) calc. C13H13N [M + H]+ 184.1121, found 184.1124.
2H), 8.02 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 7.3 Hz, 2H), 7.58−7.37 (m,
5H), 7.15 (t, J = 7.4 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 3.92 (s, 6H); 13C
NMR (101 MHz, CDCl3) δ 157.0, 155.9, 147.6, 139.4, 131.5, 129.7,
129.6, 128.9, 128.5, 127.3, 121.3, 121.0, 111.4, 55.7; HRMS (ESI) calc.
C25H21NO2 [M + H]+ 368.1645, found 368.1648.
4-Phenyl-2,6-bis(4-(trifluoromethoxy)phenyl)pyridine (3ha).
2,6-Bis(4-methylpent-3-en-1-yl)-4-phenylpyridine (3sa). In
In 90% yield (427 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 8.21
42% yield (134 mg), yellowish oil: 1H NMR (400 MHz, CDCl3)
F
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
δ 7.61 (d, J = 7.2 Hz, 2H), 7.48−7.37 (m, 3H), 7.16 (s, 2H), 5.21 (t, J =
7.1 Hz, 2H), 2.85 (t, J = 7.7 Hz, 4H), 2.45 (dd, J = 15.0, 7.4 Hz, 4H), 1.68
(s, 6H), 1.55 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 161.7, 148.7,
139.0, 132.1, 128.9, 128.6, 127.0, 123.6, 118.1, 38.5, 28.6, 25.7, 17.6;
HRMS (ESI) calc. C23H29N [M + H]+ 320.2373, found 320.2387.
4-(4-Fluorophenyl)-2,6-diphenylpyridine (3ab).9b In 92% yield
(299 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.3
Hz, 4H), 7.72 (s, 2H), 7.59 (dd, J = 8.6, 5.3 Hz, 2H), 7.48−7.36 (m, 6H),
7.12 (t, J = 8.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 163.3, 157.4,
148.9, 139.3, 134.9, 129.0, 128.8, 128.6, 127.0, 116.9, 116.0; HRMS
(ESI) calc. C23H16FN [M + H]+ 326.1340, found 326.1348.
2-(4-Methoxyphenyl)-4,6-diphenylpyridine (4a).9b In 56%
yield (189 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.18−
8.11 (m, 4H), 7.76 (d, J = 4.6 Hz, 2H), 7.67 (d, J = 7.0 Hz, 2H), 7.49−
7.37 (m, 6H), 6.99 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 160.4, 157.1, 156.9, 149.9, 139.6, 139.0, 132.1, 129.0,
128.9, 128.8, 128.6, 128.3, 127.1, 127.0, 116.3, 116.1, 113.9, 55.2; HRMS
(ESI) calc. C24H19NO [M + H]+ 338.1539, found 338.1544.
1
2-(4-Fluorophenyl)-6-(4-methoxyphenyl)-4-phenylpyridine
(4b).9b In 48% yield (170 mg), white solid: H NMR (400 MHz,
1
CDCl3) δ 8.22−8.08 (m, 4H), 7.79−7.66 (m, 4H), 7.52−7.41 (m, 3H),
7.16 (t, J = 8.7 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 163.5, 160.6, 157.1, 156.2, 150.1, 139.0, 135.7,
132.0, 129.0, 128.9, 128.8, 128.3, 127.1, 116.2, 116.0, 115.5, 114.0, 55.3;
HRMS (ESI) calc. C24H18FNO [M + H]+ 356.1445, found 356.1460.
2-(4-Methoxyphenyl)-4-phenyl-6-(thiophen-2-yl)pyridine
(4c). In 60% yield (206 mg), white solid: 1H NMR (400 MHz, CDCl3) δ
8.11 (d, J = 8.7 Hz, 2H), 7.70−7.66 (m, 5H), 7.49−7.37 (m, 4H), 7.13−
7.09 (m, 1H), 7.00 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 160.6, 156.8, 152.5, 145.0, 145.6, 138.8, 131.6, 129.0,
128.9, 128.3, 127.9, 127.5, 127.0, 124.4, 115.9, 114.5, 114.0, 55.3; HRMS
(ESI) calc. C22H17NOS [M + H]+ 344.1104, found 344.1107.
4-(3-Chlorophenyl)-2,6-diphenylpyridine (3ac). In 89% yield
1
(303 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.13 (d, J =
7.3 Hz, 4H), 7.71 (s, 2H), 7.63 (s, 1H), 7.50−7.31 (m, 9H); 13C NMR
(101 MHz, CDCl3) δ 157.4, 148.5, 140.7, 139.2, 134.9, 130.2, 129.1,
128.8, 128.6, 127.2, 127.0, 125.2, 116.7; HRMS (ESI) calc. C23H16ClN
[M + H]+ 342.1044, found 342.1047.
4-(2-Chlorophenyl)-2,6-diphenylpyridine (3ad).9b In 80% yield
1
(273 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.18 (d, J =
7.3 Hz, 4H), 7.73 (s, 2H), 7.52−7.26 (m, 10H); 13C NMR (101 MHz,
CDCl3) δ 156.8, 148.5, 139.3, 138.4, 132.2, 130.8, 130.2, 129.6, 129.0,
128.6, 127.1, 127.0, 119.3; HRMS (ESI) calc. C23H16ClN [M + H]+
342.1044, found 342.1052.
2-Cyclopropyl-6-(4-methoxyphenyl)-4-phenylpyridine (4d).
1
In 42% yield (126 mg), white solid: H NMR (400 MHz, CDCl3) δ
4-(4-Methoxyphenyl)-2,6-diphenylpyridine (3ae).9b In 90%
yield (303 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J =
7.2 Hz, 4H), 7.88 (s, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.58−7.46 (m, 6H),
7.07 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 160.4, 157.3, 149.5, 139.6, 131.1, 128.9, 128.6, 128.2, 127.1, 116.5,
114.4, 55.3; HRMS (ESI) calc. C24H19NO [M + H]+ 338.1539, found
338.1540.
8.05 (d, J = 8.8 Hz, 2H), 7.72−7.61 (m, 3H), 7.53−7.41 (m, 3H), 7.25
(s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 2.21−2.10 (m, 1H),
1.26−1.18 (m, 2H), 1.08−0.98 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 162.7, 160.3, 156.6, 149.0, 139.3, 132.4, 128.9, 128.6, 128.2, 127.1,
117.3, 114.7, 113.9, 55.3, 17.4, 9.8; HRMS (ESI) calc. C21H19NO
[M + H]+ 302.1539, found 302.1547.
General Procedure for the Synthesis of β-(Pyridin-2-yl)
Ketones. To a 10 mL tube was added a mixture of ketone 1 (1 mmol),
pyridin-2-ylmethanamine 2 (1.2 mmol), and Cu(OTf)2 (36 mg,
0.1 mmol), successively. The mixture was stirred at 80 °C for 12 h.
Upon completion, the crude product was cooled to room temperature
and then directly separated by flash column chromatography on silica
gel to give the pure product.
1-Phenyl-3-(pyridin-2-yl)propan-1-one (3j−a). In 95% yield
(200 mg), yellowish oil: 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 4.5
Hz, 1H), 7.98 (d, J = 7.6 Hz, 2H), 7.58−7.50 (m, 2H), 7.42 (t, J = 7.6 Hz,
2H), 7.25 (d, J = 8.2 Hz, 1H), 7.12−7.06 (m, 1H), 3.50 (t, J = 7.3 Hz,
2H), 3.23 (t, J = 7.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 199.2,
160.6, 149.1, 136.8, 136.4, 132.9, 128.5, 128.0, 123.3, 121.2, 37.7, 31.9;
HRMS (ESI) calc. C14H13NO [M + H]+ 212.1070, found 212.1077.
1-(4-Isobutylphenyl)-3-(pyridin-2-yl)propan-1-one (3j−b). In
93% yield (248 mg), yellowish oil: 1H NMR (400 MHz, CDCl3) δ 8.45
(d, J = 4.5 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.51 (td, J = 7.7, 1.7 Hz,
1H), 7.19 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.02 (dd, J = 7.0,
5.3 Hz, 1H), 3.43 (t, J = 7.3 Hz, 2H), 3.18 (t, J = 7.3 Hz, 2H), 2.45 (d, J =
7.2 Hz, 2H), 1.90−1.75 (m, 1H), 0.84 (d, J = 6.6 Hz, 6H); 13C NMR
(101 MHz, CDCl3) δ 198.6, 160.6, 149.0, 147.2, 136.1, 134.5, 129.0,
127.9, 123.1, 121.0, 45.1, 37.5, 31.9, 29.9, 22.1; HRMS (ESI) calc.
C18H21NO [M + H]+ 268.1696, found 268.1691.
4-(2-Methoxyphenyl)-2,6-diphenylpyridine (3af).9b In 88%
1
yield (297 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.17 (d,
J = 7.3 Hz, 4H), 7.84 (s, 2H), 7.49−7.34 (m, 8H), 7.04 (t, J = 7.5 Hz,
1H), 6.97 (d, J = 8.2 Hz, 1H), 3.78 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 156.6, 156.5, 147.8, 139.8, 130.4, 130.0, 128.7, 128.5, 128.4,
127.0, 121.0, 119.6, 111.4, 55.5; HRMS (ESI) calc. C24H19NO [M + H]+
338.1539, found 338.1548.
4-(Furan-2-yl)-2,6-diphenylpyridine (3ag).10 In 88% yield
1
(261 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.22 (d, J =
7.1 Hz, 4H), 7.95 (s, 2H), 7.61−7.45 (m, 7H), 6.99 (d, J = 3.4 Hz, 1H),
6.58 (dd, J = 3.3, 1.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 157.5,
151.9, 143.6, 139.4, 139.0, 129.0, 128.6, 127.0, 112.9, 112.1, 108.4;
HRMS (ESI) calc. C21H15NO [M + H]+ 298.1226, found 298.1229.
2,6-Diphenyl-4-(thiophen-2-yl)pyridine (3ah).10 In 95% yield
1
(297 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.19 (d, J =
7.3 Hz, 4H), 7.88 (s, 2H), 7.63 (d, J = 3.0 Hz, 1H), 7.58−7.42 (m, 7H),
7.19 (dd, J = 4.9, 3.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 157.6,
143.1, 141.8, 139.1, 129.2, 128.7, 128.4, 127.1, 127.0, 125.4, 115.4;
HRMS (ESI) calc. C21H15NS [M + H]+ 314.0998, found 314.1003.
2′,6′-Diphenyl-3,4′-bipyridine (3ai). In 65% yield (200 mg),
white solid: 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 1.3 Hz, 1H),
8.72 (d, J = 3.7 Hz, 1H), 8.20 (d, J = 7.2 Hz, 4H), 7.98 (d, J = 8.0 Hz,
1H), 7.83 (s, 2H), 7.55−7.40 (m, 7H); 13C NMR (101 MHz, CDCl3)
δ 157.6, 149.9, 148.1, 146.8, 139.0, 134.5, 134.4, 129.2, 128.6, 127.0,
123.7, 116.7; HRMS (ESI) calc. C22H16N2 [M + H]+ 309.1386, found
309.1389.
4-(Furan-2-yl)-2,6-di(thiophen-2-yl)pyridine (3lg). In 88% yield
(272 mg), white solid: 1H NMR (400 MHz, CDCl3) δ 7.76−7.69 (m,
4H), 7.59 (d, J = 1.2 Hz, 1H), 7.42 (dd, J = 5.0, 1.0 Hz, 2H), 7.14 (dd, J =
5.0, 3.7 Hz, 2H), 6.96 (d, J = 3.2 Hz, 1H), 6.57 (dd, J = 3.4, 1.8 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 152.6, 151.4, 144.7, 143.8, 139.0, 127.9,
127.9, 125.0, 112.1, 111.0, 108.9; HRMS (ESI) calc. C17H11NOS2
[M + H]+ 310.0355, found 310.0365.
1-(4-Fluorophenyl)-3-(pyridin-2-yl)propan-1-one (3j−c). In
1
86% yield (197 mg), yellowish oil: H NMR (400 MHz, CDCl3) δ
8.45 (d, J = 4.2 Hz, 1H), 8.01−7.91 (m, 2H), 7.52 (td, J = 7.7, 1.8 Hz,
1H), 7.19 (d, J = 7.8 Hz, 1H), 7.10−6.98 (m, 3H), 3.43 (t, J = 7.2 Hz,
2H), 3.18 (t, J = 7.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 197.5,
165.5, 160.4, 149.1, 136.2, 133.2, 130.5, 123.2, 121.1, 115.4, 37.4, 31.8;
HRMS (ESI) calc. C14H12FNO [M + H]+ 230.0976, found 230.0980.
1-(4-Chlorophenyl)-3-(pyridin-2-yl)propan-1-one (3j−d). In
1
82% yield (201 mg), yellowish oil: H NMR (400 MHz, CDCl3) δ
8.44 (d, J = 4.3 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.52 (td, J = 7.7, 1.8 Hz,
1H), 7.34 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 6.9,
5.3 Hz, 1H), 3.42 (t, J = 7.2 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H); 13C NMR
(101 MHz, CDCl3) δ 197.8, 160.2, 149.0, 139.1, 136.2, 135.0, 129.3,
128.6, 123.2, 121.1, 37.4, 31.7; HRMS (ESI) calc. C14H12ClNO
[M + H]+ 246.0680, found 246.0688.
1-(4-Methoxyphenyl)-3-(pyridin-2-yl)propan-1-one (3j−e). In
87% yield (210 mg), yellowish oil: 1H NMR (400 MHz, CDCl3) δ 8.45
(d, J = 4.2 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.52 (td, J = 7.7, 1.8 Hz, 1H),
1,3-Bis(2,6-diphenylpyridin-4-yl)benzene (3ap). In 78% yield
1
(418 mg), white solid: H NMR (400 MHz, CDCl3) δ 8.26 (d, J =
7.4 Hz, 8H), 8.08 (s, 1H), 7.97 (s, 4H), 7.86 (d, J = 7.6 Hz, 2H), 7.71
(t, J = 7.7 Hz, 1H), 7.56 (t, J = 7.4 Hz, 8H), 7.48 (t, J = 7.2 Hz, 4H); 13C
NMR (101 MHz, CDCl3) δ 157.7, 149.8, 140.2, 139.4, 129.9, 129.1,
128.7, 127.8, 127.1, 126.0, 117.2; HRMS (ESI) calc. C40H28N2 [M + H]+
537.2325, found 537.2342.
G
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.19 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 6.9, 5.3 Hz, 1H), 6.85 (d, J = 8.9 Hz,
2H), 3.77 (s, 3H), 3.39 (t, J = 7.3 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 197.6, 163.2, 160.7, 148.9, 136.2,
130.1, 129.8, 123.2, 121.0, 113.5, 55.2, 37.3, 32.0; HRMS (ESI) calc.
C15H15NO2 [M + H]+ 242.1176, found 242.1179.
3-(Pyridin-2-yl)-1-(thiophen-2-yl)propan-1-one (3j−f). In 76%
yield (165 mg), yellowish oil: 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J =
4.2 Hz, 1H), 7.70 (dd, J = 3.8, 0.9 Hz, 1H), 7.57−7.50 (m, 2H), 7.20 (d,
J = 7.8 Hz, 1H), 7.08−7.03 (m, 2H), 3.40 (t, J = 7.3 Hz, 2H), 3.19 (t, J =
7.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 192.1, 160.2, 149.0, 144.0,
136.3, 133.3, 131.8, 127.9, 123.2, 121.2, 38.2, 32.0; HRMS (ESI) calc.
C12H11NOS [M + H]+ 218.0634, found 218.0635.
3-(Pyridin-2-yl)-1-(pyridin-4-yl)propan-1-one (3j−g). In 68%
yield (144 mg), yellowish oil: 1H NMR (400 MHz, CDCl3) δ 8.76 (dd,
J = 4.5, 1.5 Hz, 2H), 8.46 (d, J = 4.2 Hz, 1H), 7.73 (dd, J = 4.5, 1.6 Hz,
2H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.09 (dd, J =
6.9, 5.3 Hz, 1H), 3.49 (t, J = 7.1 Hz, 2H), 3.23 (t, J = 7.0 Hz, 2H); 13C
NMR (101 MHz, CDCl3) δ 198.8, 159.7, 150.8, 149.0, 142.7, 136.5,
123.4, 121.4, 121.0, 37.7, 31.4; HRMS (ESI) calc. C13H12N2O [M + H]+
213.1022, found 213.1025.
1-(Naphthalen-1-yl)-3-(pyridin-2-yl)propan-1-one (3j−h). In
84% yield (219 mg), yellowish oil: 1H NMR (400 MHz, CDCl3) δ 8.56
(d, J = 8.5 Hz, 1H), 8.49 (d, J = 4.3 Hz, 1H), 7.95−7.90 (dd, J = 11.0, 7.8
Hz, 2H), 7.84 (d, J = 7.7 Hz, 1H), 7.59−7.42 (m, 4H), 7.24 (d, J = 7.5
Hz, 1H), 7.08 (dd, J = 6.9, 5.3 Hz, 1H), 3.56 (t, J = 7.2 Hz, 2H), 3.31 (t,
J = 7.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 203.5, 160.4,
149.1, 136.3, 136.0, 133.8, 132.4, 130.0, 128.3, 127.7, 127.4, 126.3, 125.8,
124.3, 123.2, 121.1, 40.9, 32.4; HRMS (ESI) calc. C18H15NO [M + H]+
262.1226, found 262.1237.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(20932002 and 21172076), National Basic Research Program of
China (973 Program) (2011CB808600), Guangdong Natural
Science Foundation (10351064101000000 and S2012040007088),
China Postdoctoral Science Foundation (2012T50673) and the
Fundamental Research Funds for the Central Universities
(2012ZP0003 and 2012ZB0011) for financial support.
REFERENCES
■
(1) (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337. (c) Su, S.-J.; Chiba, T.; Takeda, T.; Kido, J. Adv.
Mater. 2008, 20, 2125. (d) Sasabe, H.; Kido, J. Chem. Mater. 2011, 23,
621. (e) Wang, Y.; Daniher, A.; De Klerk, A.; Winkel, C. Pyridine
Derivatives with Umami Flavour. US 20120121783, May 17, 2012.
(2) For recent and representative examples of pyridine synthesis, see:
(a) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592.
(b) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
129, 10096. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 3645. (d) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc.
2008, 130, 6918. (e) Manning, J. R.; Davies, H. M. L. J. Am. Chem. Soc.
2008, 130, 8602. (f) Donohoe, T. J.; Jones, C. R.; Barbosa, L. C. A. J. Am.
Chem. Soc. 2011, 133, 16418. (g) Chen, M. Z.; Micalizio, G. C. J. Am.
Chem. Soc. 2012, 134, 1352. (h) Gati, W.; Rammah, M. M.; Rammah, M.
B.; Couty, F.; Evano, G. J. Am. Chem. Soc. 2012, 134, 9078.
(3) Theodoridis, G. Tetrahedron 2000, 56, 2339.
(4) For recent examples of C−C bond formation by C−N bond
cleavage, see: (a) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M.
2-(Pyridin-2-ylmethyl)cyclohexanone (3j−i). In 69% yield (130
mg), yellowish oil: 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 4.8 Hz,
1H), 7.56 (td, J = 7.7, 1.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.08 (dd, J =
6.8, 5.2 Hz, 1H), 3.34 (dd, J = 14.2, 6.1 Hz, 1H), 3.07−2.93 (m, 1H),
2.58 (dd, J = 14.2, 7.4 Hz, 1H), 2.47−2.30 (m, 2H), 2.13−2.01 (m, 2H),
1.88−1.78 (m, 1H), 1.73−1.60 (m, 2H), 1.48−1.35 (m, 1H); 13C NMR
(101 MHz, CDCl3) δ 212.2, 160.3, 149.0, 136.0, 123.9, 120.9, 50.6, 42.1,
37.7, 34.0, 28.0, 25.1; HRMS (ESI) calc. C12H15NO [M + H]+ 190.1226,
found 190.1242.
̃
Chem. Rev. 2006, 106, 4622. (b) Taylor, J. G.; Moro, A. V.; Correia, C. R.
Eur. J. Org. Chem. 2011, 1403. (c) Koreeda, T.; Kochi, T.; Kakiuchi, F. J.
Am. Chem. Soc. 2009, 131, 7238. (d) Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P.
Org. Lett. 2011, 13, 6308. (e) Saeki, T.; Son, E.-C.; Tamao, K. Org. Lett.
2004, 6, 617. (f) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 6046. (g) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.; Huang, H. J. Am.
Chem. Soc. 2012, 134, 20613. For recent examples of C−N bond
formation by C−N bond cleavage, see: (h) Ding, S.; Jiao, N. Angew.
Chem., Int. Ed. 2011, 50, 9226. (i) Guo, S.; Qian, B.; Xie, Y.; Xia, C.;
Huang, H. Org. Lett. 2011, 13, 522. (j) Kuninobu, Y.; Nishi, M.; Takai, K.
Chem. Commun. 2010, 8860. (k) Geng, W.; Zhang, W.-X.; Hao, W.; Xi,
Z. J. Am. Chem. Soc. 2012, 134, 20230.
2-Methyl-1-(pyridin-2-yl)pentan-3-one (3j−j). In 65% yield
1
(115 mg), yellowish oil: H NMR (400 MHz, CDCl3) δ 8.50 (d, J =
4.7 Hz, 1H), 7.56 (td, J = 7.6, 1.7 Hz, 1H), 7.14−7.06 (m, 2H), 3.23−
3.14 (m, 2H), 2.82−2.68 (m, 1H), 2.58−2.33 (m, 2H), 1.11 (d, J = 6.8,
Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 214.5,
159.6, 149.1, 136.1, 123.6, 121.1, 45.5, 40.9, 34.7, 16.6, 7.6; HRMS (ESI)
calc. C11H15NO [M + H]+ 178.1226, found 178.1235.
(5) (a) Weng, Z.-T.; Li, Y.; Tian, S.-K. J. Org. Chem. 2011, 76, 8095.
(b) Yang, C.-F.; Wang, J.-Y.; Tian, S.-K. Chem. Commun. 2011, 47, 8343.
(c) Sun, F.-L.; Zheng, X.-J.; Gu, Q.; He, Q.-L.; You, S.-L. Eur. J. Org.
2-Methyl-1-phenyl-3-(pyridin-2-yl)propan-1-one (3j−k). In
1
́ ́
Chem. 2010, 47. (d) Esquivias, J.; Gomez-Arrayas, R.; Carretero, J. C.
95% yield (214 mg), yellowish oil: H NMR (400 MHz, CDCl3) δ
Angew. Chem., Int. Ed. 2006, 45, 629. (e) Yang, B.-L.; Tian, S.-K. Chem.
Commun. 2010, 46, 6180. (f) Liu, C.-R.; Yang, F.-L.; Jin, Y.-Z.; Ma, X.-T.;
Cheng, D.-J.; Li, N.; Tian, S.-K. Org. Lett. 2010, 12, 3832.
8.43 (d, J = 5.5 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.48−7.31 (m, 4H),
7.08 (d, J = 7.8 Hz, 1H), 6.98 (dd, J = 7.0, 5.4 Hz, 1H), 4.15−4.06 (m,
1H), 3.29 (dd, J = 14.0, 7.1 Hz, 1H), 2.81 (dd, J = 14.0, 7.0 Hz, 1H), 1.16
(d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 203.5, 159.5, 149.1,
136.2, 135.9, 132.6, 128.3, 128.2, 123.7, 121.0, 41.2, 40.6, 17.4; HRMS
(ESI) calc. C15H15NO [M + H]+ 226.1226, found 226.1229.
(6) Wang, Y.; Chi, Y.; Zhang, W.; Xi, Z. J. Am. Chem. Soc. 2012, 134,
2926.
(7) For some reviews on the Cu/O2 system, see (a) Lewis, E. A.;
Tolman, W. B. Chem. Rev. 2004, 104, 1047. (b) Wendlandt, A. E.; Suess,
A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062. (c) Shi, Z.;
Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (d) Zhang,
C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
(8) For copper-catalyzed imine synthesis from benzylamines, see:
(a) Tian, H.; Yu, X.; Li, Q.; Wang, J.; Xu, Q. Adv. Synth. Catal. 2012, 354,
2671. (b) Largeron, M.; Fleury, M.-B. Angew. Chem., Int. Ed. 2012, 51,
5409. (c) Hu, Z.; Kerton, F. M. Org. Biomol. Chem. 2012, 10, 1618.
(d) Patil, R. D.; Adimurthy, S. RSC Adv. 2012, 2, 5119. (e) Patila, R. D.;
Adimurthy, S. Adv. Synth. Catal. 2011, 353, 1695.
(9) For pyridine synthesis by carbonyl condensation, see: (a) Bagley,
M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459. (b) Ren, Z.-H.;
Zhang, Z.-Y.; Yang, B.-Q.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2011, 13,
5394. (c) Wang, Q.; Wan, C.; Gu, Y.; Zhang, J.; Gao, L.; Wang, Z. Green
Chem. 2011, 13, 578. (d) Li, J.; He, P.; Yu, C. Tetrahedron 2012, 68,
4138. (e) Krohnke, F. Synthesis 1976, 1.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details and copies of NMR spectral data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jianghf@scut.edu.cn. Fax: (+86)-20-8711-2906.
Notes
The authors declare no competing financial interest.
H
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(10) Adib, M.; Tahermansouri, H.; Koloogani, S. A.; Mohammadi, B.;
Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47, 5957.
(11) Liu, B.; Bao, Y.; Du, F.; Wang, H.; Tian, J.; Bai, R. Chem. Commun.
2011, 47, 1731.
(12) Nagarapu, L.; Aneesa; Peddiraju, R.; Apuri, S. Catal. Commun.
2007, 8, 1973.
(13) Upta, A. K.; Ila, H.; Junjappa, H. Tetrahedron 1990, 46, 2561.
I
dx.doi.org/10.1021/jo400261v | J. Org. Chem. XXXX, XXX, XXX−XXX