Simple selective synthesis of 2,4- and 2,6-diarylpyridines through metal-free cyclocondensation of aromatic ketones with ammonium acetate

Article abstract of DOI:10.1055/s-0030-1258274

A simple and selective one-pot synthesis of 2,4- and 2,6-diarylpyridines through the cyclocondensation reaction of aromatic ketones with ammonium acetate has been developed. The procedure is metal-free, convenient, and efficient, and the substrates are re

Full text of DOI:10.1055/s-0030-1258274

4228
PAPER
Simple Selective Synthesis of 2,4- and 2,6-Diarylpyridines through Metal-Free
Cyclocondensation of Aromatic Ketones with Ammonium Acetate
Synthesis
iof 2,4-
n
and 2,6-Diarylpyri
L
dines iu, Chuanxin Wang, Liansheng Wu, Fen Liang, Guosheng Huang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: hgs2368@163.com
Received 10 August 2010; revised 3 September 2010
pen between aromatic ketones and ammonia. In this pa-
Abstract: A simple and selective one-pot synthesis of 2,4- and 2,6-
diarylpyridines through the cyclocondensation reaction of aromatic
ketones with ammonium acetate has been developed. The procedure
is metal-free, convenient, and efficient, and the substrates are readi-
ly available.
per, we present a simple, convenient and efficient
synthesis of 2,4- and 2,6-diarylpyridines through a cyclo-
condensation reaction of acetophenones with ammonium
acetate (Scheme 1), which appears to be a promising strat-
egy for the direct, metal-free, and selective synthesis of
2,4- and 2,6-diarylpyridines from readily available sub-
strates.
Key words: diarylpyridines, selective, cyclocondensation, aromat-
ic ketones, ammonium acetate
N
Ar
Pyridine derivatives have attracted a great deal of interest,
not only for their abundance in natural products and syn-
thetic pharmaceuticals,1 but also because they have many
applications including agrochemicals,2 ligands for met-
als,3 homogeneous catalysis,4 aromatase inhibitors,5 anti-
HIV agents,6 and anti-cancer drugs.7 Furthermore, they
have played an increasingly important part in research
fields such as coordination chemistry,8 supramolecular
chemistry,9 materials science,10 as well as for asymmetric
synthesis.11
Ar
N
Ar
R
NH4OAc
NH4OAc
O
DMSO
120 °C, 24 h
R
DMSO
120 °C, 24 h
R
Ar
Ar
R = Me, Et, Ph
R = H
Scheme 1 Simple selective synthesis of 2,4- and 2,6-diarylpyri-
dines
An initial study was performed to optimize the reaction
conditions. The impact of the source of ammonia, solvent,
and temperature was investigated in detail for the reaction
(Table 1). In these experiments, we used 4-methoxyace-
tophenone (1a) as a model reactant. The results indicated
that the solvent had a profound effect on the formation of
2a, with dimethyl sulfoxide proving to be the solvent of
choice (entries 1–10). The source of ammonia was also
examined (entries 11–15) and it was shown that the reac-
tion can also take place in the presence of several ammo-
nium salts [NH4OAc, NH4HCO3, HCO2NH4, (NH4)2CO3]
or an organic ammonia source, such as urea; ammonium
acetate gave the best result. In addition, to optimize fur-
ther the reaction conditions, the same reaction was carried
out in dimethyl sulfoxide at temperatures ranging from 80
to 140 °C (Table 1, entries 16–18), with 120 °C chosen to
be the reaction temperature.
Not surprisingly, pyridine synthesis, to which a great deal
of work has been devoted by chemists until recently, has
long occupied a significant place in organic synthesis, re-
sulting in the development of a wide range of synthetic
methods.12–15 Among the various reported approaches to
pyridines, vapor-phase cyclization of acetophenone,
formaldehyde, and ammonia,16 arylation of the pyridine
nucleus with organometallic reagents,17 and palladium-
catalyzed direct arylation of pyridine N-oxides18 are con-
sidered to be the three available routes to diarylpyridines.
Nevertheless, they suffer from many limitations such as
complicated procedures, harsh reaction conditions, the re-
quirement for a metal, and substrates that are not readily
available. Consequently, it is desirable to find new, effi-
cient methods for the construction of diarylpyridines.
For the optimal reaction conditions, 1 was reacted with
ammonium acetate (3 equiv) in dimethyl sulfoxide (1 mL)
at 120 °C for 24 hours and these conditions were subse-
quently employed when examining the substrate scope of
the reaction (Table 2). Gratifyingly, a variety of acetophe-
nones 1a–q successfully reacted under the aforesaid con-
ditions to afford the desired 2,4-diarylpyridines 2a–q in
good yields.
In 1953, Ernest L. Eliel et al. reported a condensation re-
action of phenylacetaldehyde with ammonia,19 which was
considered to be an abnormal Chichibabin reaction be-
cause of its unexpected 3,5-diphenylpyridine product.
Perhaps because of its inefficiency, to the best of our
knowledge, there have been few investigations on the util-
ity of this reaction for the synthesis of diarylpyridines.
Enlightened by this abnormal Chichibabin reaction, it was
assumed that a similar condensation reaction would hap-
Notably, various electron-rich acetophenones (Table 2,
entries 1, 3, 4, 10, 11, 16, 17) and some electron-deficient
acetophenones (entries 6, 7, 13) as well as others that have
well-conjugated structures (entries 14, 15) are suitable
substrates for the reaction. Conversely, other electron-
SYNTHESIS 2010, No. 24, pp 4228–4234
x
x.
x
x
.
2
0
1
0
Advanced online publication: 28.09.2010
DOI: 10.1055/s-0030-1258274; Art ID: F14310SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2,4- and 2,6-Diarylpyridines
4229
Table 1 Screening the Impact of Solvent, Ammonia Source, and
Table 2 Synthesis of 2,4-Diarylpyridines 2 from 1-Substituted Eth-
anones 1a
Temperaturea
R
N
N
O
NH4OAc (3 equiv)
MeO
O
DMSO, 120 °C, 24 h
R
ammonia source (3 equiv)
R
solvent, 80–140 °C, 24 h
MeO
1
2
2a
1a
Entry
1
R
Product
2a
2b
2c
Yieldb (%)
86
OMe
Entry Ammonia sourceb Solvent
Temp
(°C)
Yieldc
(%)
4-MeOC6H4
Ph
2
74
1
2
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4HCO3
NH4Cl
DMF
120
120
120
120
120
120
120
45
38
trace
trace
20
15
42
53
70
86
25
0
3
4-MeC6H4
4-PhOC6H4
4-HOC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
76
AcOH
toluene
MeNO2
MeCN
dioxane
NMP
4
2d
2e
83
3
5c
53
4
6
2f
72
5
7
2g
2h
2i
71
6
8c
55
7
9c
4-HC≡CC6H4
3-MeC6H4
3-MeOC6H4
3-O2NC6H4
3-BrC6H4
4-PhC≡CC6H4
4-PhC6H4
3,4-Me2C6H3
3,5-Me2C6H3
2-MeC6H4
2-HOC6H4
2-pyridyl
Et
50
8
AcOH–glycol (1:2) 120
10
11
12c
13
14
15
16
17
18c
19c
20c
21
22
2j
72
9
glycol
120
120
120
120
120
120
120
80
2k
2l
73
10
11
12
13
14
15
16
17
18
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
53
2m
2n
2o
2p
2q
2r
70
90
HCO2NH4
(NH4)2CO3
CO(NH2)2
NH4OAc
NH4OAc
NH4OAc
45
60
53
62
73
86
88
82
70
trace
trace
trace
0
100
140
2s
2t
a Reaction conditions: 1a (0.45 mmol), ammonia source (3 equiv),
solvent (1 mL), 80–140 °C, 24 h.
2u
b Excess ammonia was required to achieve satisfactory isolated yields
and 3 equiv was a reasonable amount of the ammonia source; the op-
timization details are not presented in this table.
Fcd
2v
0
a Reaction conditions: 1 (0.45 mmol), NH4OAc (3 equiv), DMSO (1
mL), 120 °C, 24 h.
c Isolated yield after column chromatography.
b Isolated yield after column chromatography.
c The reaction time was increased to 36 h.
d Ferrocenyl.
deficient acetophenones (entries 5, 8, 9, 12) generated
their cyclocondensation products in moderate yields only.
In addition, 2¢-substituted acetophenones, possibly be-
cause of steric hindrance, gave only traces of products
(entries 18, 19), moreover, other heterocyclic ketones
such as methyl 2-pyridyl ketone (1t) also gave only a trace
of product (entry 20). Unfortunately, when butan-2-one
(1u) and ferrocenyl methyl ketone (1v) were employed,
the desired product was completely absent (entries 21,
22).
3,5-disubstituted 2,6-diarylpyridines could be prepared
when 2-substituted acetophenones were employed in this
reaction (Table 3). In particular, electron-rich 2-substitut-
ed acetophenones were superior to electron-deficient 2-
substituted acetophenones. Reaction with electron-rich 2-
substituted acetophenones afforded the corresponding cy-
clocondensation products in good yields (70–75%, entries
2, 3), while relatively electron-deficient 2-substituted ace-
tophenones gave the corresponding products in moderate
yields (56–60%, entries 4, 5). The structure of compound
4g (Figure 1) was confirmed by single-crystal X-ray anal-
Encouraged by the results obtained, a subsequent study
was carried out to evaluate further the substrate scope of
this reaction. It was consistent with our conjecture that
Synthesis 2010, No. 24, 4228–4234 © Thieme Stuttgart · New York

4230
J. Liu et al.
PAPER
Table 3 Synthesis of 3,5-Disubstituted 2,6-Diarylpyridines 4 from
2-Substituted Acetophenones 3a
O
Ar
N
Ar
NH4OAc (3 equiv)
R
Ar
DMSO, 120 °C, 24 h
R
R
3
4
Entry
Ar
Ph
R
Product
4a
Yieldb (%)
1
2
3
4
5
6
7
Me
62
70
75
60
56
50
55
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-ClC6H4
Ph
Me
Me
Me
Me
Et
4b
4c
4d
4e
4f
Ph
Ph
4g
a Reaction conditions: 3 (0.45 mmol), NH4OAc (3 equiv), DMSO (1
mL), 120 °C, 24 h.
Figure 1 X-ray crystal structure of 4g
b Isolated yield after column chromatography.
A plausible mechanism is proposed in Scheme 2 that is
based on previous reports19,20 combined with our experi-
ments results. Initially, the condensation of the acetophe-
none with itself gives A, which then undergoes a Michael
Addition with another molecule of acetophenone leading
to 1,5-dicarbonyl compound B. Condensation reaction of
B in the presence of ammonium acetate affords dihydro-
pyridine intermediates C and D. Oxidative aromatization
with removal of methane from C would yield 2,4,6-tri-
arylpyridine G, and D forms another two dihydropyridine
intermediates E and F by removal of the methyl group.
ysis. In addition, steric hindrance by the 2-substituent in
the acetophenones makes the corresponding substrates
not well suited to the reaction (entries 6, 7). It is likely that
the effects of steric hindrance within these substrates in
the reaction make their cyclocondensation products differ
from those above (Table 2) and may be a interpretation of
why they provide the 3,5-disubstituted 2,6-diarylpy-
ridines products in moderate yields only.
O
+
Ar
O
Ar
– H2O
Ar
O
O
Ar
Ar
Ar
N
Ar
Ar
N
Ar
A
– CH4
H
Ar
Ar
(minor)
Ar
G
O
O
Ar
Ar
C
NH4OAc
N
Ar
N
Ar
Ar
– ArH
– AcOH
– 2 H2O
Ar
H
H
N
B
H
E
Ar
Ar
H+
Ar
H2O
(minor)
Ar
CH3OH
OH-
H
N
N
Ar
Ar
Ar
– ArH
D
Ar
Ar
I
F
(major)
Scheme 2 Proposed mechanism for the cyclocondensation reaction
Synthesis 2010, No. 24, 4228–4234 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,4- and 2,6-Diarylpyridines
4231
13C NMR (100 MHz, CDCl3): d = 160.44, 157.60, 149.84, 148.60,
132.19, 130.86, 128.23, 128.16, 119.04, 117.36, 114.48, 114.08,
55.34, 55.30.
HRMS (ESI): m/z [M + H]+ calcd for C19H18NO2: 292.1332; found:
292.1335.
Then, oxidative aromatization with removal one of the
three aryl groups on the 2,4,6-triaryldihydropyridines E
and F would provide the two diarylpyridine isomers H
and I, respectively. In fact, minor 2,4,6-tris(4-methoxy-
phenyl)pyridine (G) and 2,6-bis(4-methoxyphenyl)pyri-
dine (H) were detected by GC-MS in the reaction mixture
of 4-methoxyacetophenone (1a) and ammonium acetate.
In this reaction, it can be seen that ammonium acetate
serves not only as a reactant but also as a catalyst.20c The
reaction pathway of 2-substituted acetophenones 3 in this
reaction yielding 3,5-disubstituted 2,6-diarylpyridines 4 is
similar to this proposed mechanism.
2,4-Diphenylpyridine (2b)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2b
(74% yield) as a yellow oil.
IR (neat): 3384.40, 2925.59, 1597.09, 694.46 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.732 (d, J = 5.2 Hz, 1 H), 8.036–
8.059 (dd, J = 8.2 Hz, 1 Hz, 2 H), 7.922 (s, 1 H), 7.672–7.696 (m, 2
H), 7.427–7.521 (m, 7 H).
In summary, a simple, convenient, and efficient method
for the one-pot synthesis of 2,4- and 2,6-diarylpyridines
from readily available aromatic ketones and ammonium
acetate has been developed in our laboratory. The reaction
is selective, no metal catalysts are required, and it allows
the construction of aryl-substituted pyridines of both bio-
logical and synthetic interest. Many substrates are suitable
for this procedure, affording various 2,4- and 2,6-di-
arylpyridines in moderate to good yields. This strategy
may be very useful for the synthesis of 2,4- and 2,6-di-
arylpyridines and the corresponding natural products. A
more detailed investigation on the mechanism and scope
of this reaction, as well as the utilization of this reaction in
the synthesis of complex molecules is ongoing in our lab-
oratory and will be reported in due course.
13C NMR (100 MHz, CDCl3): d = 158.08, 150.07, 149.26, 139.49,
138.53, 129.09, 129.00, 128.74, 127.05, 127.01, 120.22, 118.72.
HRMS (ESI): m/z [M + H]+ calcd for C17H14N: 232.1121; found:
232.1117.
2,4-Di-4-tolylpyridine (2c)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2c
(76% yield) as an off-white solid; mp 91–93 °C.
IR (KBr): 3026.16, 1597.30, 809.10 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.686 (d, J = 5.2 Hz, 1 H), 7.941
(d, J = 8.0 Hz, 2 H), 7.881 (s, 1 H), 7.580 (d, J = 8.0 Hz, 2 H),
7.382–7.398 (dd, J = 4.8 Hz, 1.6 Hz, 1 H), 7.293 (d, J = 6.8 Hz, 4
H), 2.412 (s, 3 H), 2.409 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 157.96, 149.87, 149.12, 139.09,
138.96, 136.69, 135.63, 129.79, 129.46, 126.87, 119.73, 118.18,
21.25, 21.20.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N: 260.1434; found:
260.1435.
NMR spectra were recorded on 400 MHz in CDCl3 or acetone-d6
and 13C NMR spectra were recorded on 100 MHz in CDCl3 or
DMSO-d6 using TMS as internal standard. IR spectra were recorded
on a FT-IR spectrophotometer and only major peaks are reported in
cm–1. Melting points were determined on a microscopic apparatus
and were uncorrected. All products were further characterized by
ESI HRMS; copies of their 1H NMR and 13C NMR spectra are pro-
vided. All materials were purchased from common commercial
sources and used without additional purification. Petroleum ether =
PE.
2,4-Bis(4-phenoxyphenyl)pyridine (2d)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2d
(83% yield) as a light-yellow solid; mp 186–188 °C.
IR (KBr): 3381.75, 3061.18, 1591.69, 1488.27, 1238.26, 827.13
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.682 (d, J = 5.2 Hz, 1 H), 8.017
(d, J = 8.8 Hz, 2 H), 7.850 (s, 1 H), 7.648 (d, J = 8.4 Hz, 2 H),
7.333–7.393 (m, 5 H), 7.054–7.171 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 158.52, 158.31, 157.47, 156.87,
156.54, 150.03, 148.53, 134.50, 133.15, 129.89, 129.79, 128.53,
128.46, 123.86, 123.53, 119.58, 119.39, 119.16, 118.95, 118.83,
117.90.
2,4-Bis(4-methoxyphenyl)pyridine (2a) and 3,5-Dimethyl-2,6-
diphenylpyridine (4a); Typical Procedures
All reactions were performed on a 0.45-mmol scale relative to 1a
and 3a. To a soln of NH4OAc (3 equiv) in DMSO (1 mL) in a 10-
mL general monomodal reaction vial was added 4-methoxyace-
tophenone (0.45 mmol) or propiophenone (0.45 mmol). The reac-
tion vial was sealed and heated in an oil bath at 120 °C for 24 h with
stirring (TLC monitoring). To the mixture was added H2O (2 mL)
and it was extracted with EtOAc (3 × 10 mL). The combined organ-
ic phases were washed with brine (2 × 5 mL), dried (anhyd MgSO4),
and concentrated in vacuo. The residue was subjected to flash col-
umn chromatography (silica gel, PE–EtOAc, 12:1) to gave 2a (37.6
mg, 86%) and 4a (23.5 mg, 62%), respectively.
HRMS (ESI): m/z [M + H]+ calcd for C29H22NO2: 416.1645; found:
416.1647.
2,4-Bis(4-hydroxyphenyl)pyridine (2e)
Purified by flash chromatography (PE–EtOAc, 4:1) to give 2e (53%
yield) as a yellow solid; mp 206–208 °C.
IR (KBr): 3421.04, 1652.00, 1026.78, 628.39 cm–1.
1H NMR (400 MHz, acetone-d6): d = 9.796 (s, 1 H), 9.693 (s, 1 H),
8.553 (d, J = 5.2 Hz, 1 H), 8.034 (s, 1 H), 8.004 (d, J = 7.6 Hz, 2 H),
7.750 (d, J = 8.4 Hz, 2 H), 7.454–7.471 (dd, J = 5.2 Hz, 1.6 Hz, 1
H), 6.858–6.917 (m, 4 H).
2,4-Bis(4-methoxyphenyl)pyridine (2a)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2a
(86% yield) as an off-white solid; mp 147–149 °C.
13C NMR (100 MHz, DMSO-d6): d = 158.60, 158.43, 156.76,
149.66, 147.77, 129.85, 128.19, 128.09, 128.01, 118.08, 115.84,
115.53, 115.34.
HRMS (ESI): m/z [M + H]+ calcd for C17H14NO2: 264.1019; found:
264.1013.
IR (KBr): 3400.98, 2959.05, 1606.13, 1515.86, 1249.42, 1020.12,
813.92 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.644 (d, J = 5.2 Hz, 1 H), 7.995
(d, J = 8.4 Hz, 2 H), 7.821 (s, 1 H), 7.630 (d, J = 8.8 Hz, 2 H), 7.338
(d, J = 5.2 Hz, 1 H), 7.009 (d, J = 4.2 Hz, 4 H), 3.857 (s, 6 H).
Synthesis 2010, No. 24, 4228–4234 © Thieme Stuttgart · New York

4232
J. Liu et al.
PAPER
2,4-Bis(4-chlorophenyl)pyridine (2f)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2f
(72% yield) as a red-brown solid; mp 102–104 °C.
13C NMR (100 MHz, CDCl3): d = 158.20, 149.95, 149.39, 139.52,
138.79, 138.58, 138.41, 129.74, 128.99, 128.63, 127.78, 127.75,
124.19, 124.12, 120.19, 118.82, 21.51, 21.49.
IR (KBr): 2923.04, 1595.72, 1091.31, 814.73 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N: 260.1434; found:
260.1436.
1H NMR (400 MHz, CDCl3): d = 8.715 (d, J = 4.8 Hz, 1 H), 7.982
(d, J = 8.4 Hz, 2 H), 7.830 (s, 1 H), 7.601 (d, J = 8.4 Hz, 2 H),
7.442–7.483 (m, 4 H), 7.389–7.405 (dd, J = 5 Hz, 1.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 156.98, 150.28, 148.18, 137.68,
136.77, 135.41, 135.31, 129.36, 128.95, 128.31, 128.26, 120.20,
118.17.
2,4-Bis(3-methoxyphenyl)pyridine (2k)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2k
(73% yield) as an orange oil.
IR (neat): 2931.95, 1590.78, 1464.30, 1280.08, 1042.08, 782.77
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.723 (d, J = 4.8 Hz, 1 H), 7.901
(s, 1 H), 7.632 (d, J = 2 Hz, 1 H), 7.600 (d, J = 8 Hz, 1 H); 7.378–
7.436 (m, 3 H), 7.275 (s, 1 H), 7.204 (d, J = 1.6 Hz, 1 H), 6.974–
7.007 (m, 2 H), 3.904 (s, 3 H), 3.883 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.15, 160.07, 157.82, 149.95,
149.16, 140.92, 139.97, 130.15, 129.71, 120.41, 119.47, 119.39,
118.90, 115.12, 114.27, 112.88, 112.16, 55.37.
HRMS (ESI): m/z [M + H]+ calcd for C17H12Cl2N: 300.0341; found:
300.0345.
2,4-Bis(4-bromophenyl)pyridine (2g)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2g
(71% yield) as an orange solid; mp 137–139 °C.
IR (KBr): 3391.09, 3147.95, 1593.16, 1374.53, 1070.73, 1006.06,
811.68 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.720 (d, J = 5.2 Hz, 1 H), 7.919
(d, J = 8.8 Hz, 2 H), 7.836 (s, 1 H), 7.605–7.648 (m, 4 H), 7.527–
7.554 (m, 2 H), 7.401–7.418 (dd, J = 5.2 Hz, 1.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 157.05, 150.33, 148.26, 138.12,
137.23, 132.34, 131.93, 128.61, 128.55, 123.67, 123.64, 120.22,
118.11.
HRMS (ESI): m/z [M + H]+ calcd for C19H18NO2: 292.1332; found:
292.1334.
2,4-Bis(3-nitrophenyl)pyridine (2l)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2l
(53% yield) as a red-brown solid; mp 197–199 °C.
IR (KBr): 3371.68, 3085.71, 1525.90, 1351.61, 731.06 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.946 (s, 1 H), 8.868 (d, J = 5.2
Hz, 1 H), 8.572 (s, 1 H), 8.461 (d, J = 8 Hz, 1 H), 8.311–8.370 (m,
2 H), 8.025–8.059 (m, 2 H), 7.688–7.770 (m, 2 H), 7.582 (d, J = 4
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 155.92, 150.89, 148.95, 148.87,
147.39, 140.59, 139.82, 133.01, 132.86, 130.39, 129.88, 124.01,
123.98, 122.11, 121.95, 121.25, 118.61.
HRMS (ESI): m/z [M + H]+ calcd for C17H12Br2N: 387.9331; found:
387.9338.
2,4-Bis(4-iodophenyl)pyridine (2h)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2h
(55% yield) as an off-white solid; mp 171–173 °C.
IR (KBr): 3384.64, 2922.09, 11596.48, 1372.21, 1001.52, 808.94
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.717 (d, J = 4.8 Hz, 1 H), 7.815–
7.851 (m, 5 H), 7.778 (d, J = 8.4 Hz, 2 H), 7.391–7.412 (m, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H12N3O4: 322.0822; found:
322.0827.
13C NMR (100 MHz, CDCl3): d = 157.16, 150.35, 148.36, 138.72,
138.32, 137.92, 137.83, 128.76, 128.72, 120.23, 118.00, 95.55,
95.34.
HRMS (ESI): m/z [M + H]+ calcd for C17H12I2N: 483.9054; found:
483.9052.
2,4-Bis(3-bromophenyl)pyridine (2m)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2m
(70% yield) as an orange solid; mp 94–96 °C.
IR (KBr): 3061.94, 2924.29, 1591.38, 1542.39, 1461.63, 783.31
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.735 (d, J = 5.2 Hz, 1 H), 8.210
(s, 1 H), 7.961 (d, J = 8 Hz, 1 H), 7.803–7.826 (m, 2 H), 7.545–
7.599 (m, 3 H), 7.333–7.421 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 156.64, 150.33, 147.99, 141.20,
140.38, 132.08, 130.65, 130.27, 130.12, 130.10, 125.71, 125.53,
123.29, 123.09, 120.63, 118.57.
2,4-Bis(4-ethynylphenyl)pyridine (2i)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2i
(50% yield) as an orange oil.
IR (neat): 3290.05, 1598.16, 1468.05, 824.22 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.746 (d, J = 5.2 Hz, 1 H), 8.027
(d, J = 8.4 Hz, 2 H), 7.899 (s, 1 H), 7.609–7.664 (m, 6 H), 7.430–
7.446 (dd, J = 4.8 Hz, 1.6 Hz, 1 H), 3.189 (s, 1 H), 3.173 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 157.21, 150.33, 148.44, 139.52,
138.63, 132.87, 132.57, 126.99, 126.87, 123.07, 122.86, 120.37,
118.54, 83.46, 83.02, 78.80, 78.45.
HRMS (ESI): m/z [M + H]+ calcd for C17H12Br2N: 387.9331; found:
387.9336.
2,4-Bis[4-(phenylethynyl)phenyl]pyridine (2n)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2n
(90% yield) as a yellow solid; mp 183–185 °C.
HRMS (ESI): m/z [M + H]+ calcd for C21H14N: 280.1121; found:
280.1124.
IR (KBr): 3371.31, 2921.87, 1591.95, 1413.08, 821.24, 750.65,
687.56 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.744 (d, J = 4.8 Hz, 1 H), 8.065
(d, J = 8.4 Hz, 2 H), 7.933 (s, 1 H), 7.652–7.673 (m, 6 H), 7.553–
7.572 (m, 4 H), 7.436–7.452 (dd, J = 5 Hz, 1.4 Hz, 1 H), 7.343–
7.369 (m, 6 H).
2,4-Di-3-tolylpyridine (2j)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2j
(72% yield) as an orange oil.
IR (neat): 2920.39, 1593.85, 784.40 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.713 (d, J = 5.2 Hz, 1 H), 7.894
(d, J = 6.8 Hz, 2 H), 7.816 (d, J = 8 Hz, 1 H), 7.486 (d, J = 6.8 Hz,
2 H), 7.359–7.428 (m, 3 H), 7.236–7.274 (m, 2 H), 2.452 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 157.27, 150.27, 148.46, 138.95,
137.95, 132.31, 132.03, 131.66, 131.64, 128.52, 128.40, 128.36,
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Synthesis of 2,4- and 2,6-Diarylpyridines
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126.99, 126.90, 124.27, 124.05, 123.17, 122.98, 120.21, 118.41,
91.10, 90.80, 89.28, 88.82.
HRMS (ESI): m/z [M + H]+ calcd for C33H22N: 432.1747; found:
IR (KBr): 3381.74, 2922.33, 1426.51, 908.12, 825.74, 731.89 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.480 (d, J = 8 Hz, 4 H), 7.429 (s,
1 H), 7.219 (d, J = 8 Hz, 4 H), 2.380 (s, 6 H), 2.363 (s, 6 H).
432.1744.
13C NMR (100 MHz, CDCl3): d = 155.67, 141.04, 137.90, 137.25,
129.12, 128.71, 128.66, 21.23, 19.66.
2,4-Bis(biphenyl-4-yl)pyridine (2o)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2o
(88% yield) as a light-yellow solid; mp 208–210 °C.
HRMS (ESI): m/z [M + H]+ calcd for C21H22N: 288.1747; found:
288.1739.
IR (KBr): 3404.79, 1590.58, 1443.90, 1378.92, 759.88, 689.95
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.762 (d, J = 4.8 Hz, 1 H), 8.150
(d, J = 8.4 Hz, 2 H), 8.012 (s, 1 H), 7.728–7.794 (m, 6 H), 7.644–
7.679 (m, 4 H), 7.444–7.493 (m, 5 H), 7.348–7.403 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 157.70, 150.18, 148.79, 141.99,
141.82, 140.57, 140.25, 138.35, 137.30, 128.91, 128.82, 127.82,
127.74, 127.53, 127.47, 127.43, 127.10, 120.07, 118.41.
2,6-Bis(4-methoxyphenyl)-3,5-dimethylpyridine (4c)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 4c
(75% yield) as an off-white solid; mp 108–110 °C.
IR (KBr): 2954.70, 1609.09, 1511.77, 1461.20, 1426.64, 1247.75,
1176.39, 1028.78, 837.19 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.558 (d, J = 8.8 Hz, 4 H), 7.432
(s, 1 H), 6.970 (d, J = 8.8 Hz, 4 H), 3.849 (s, 6 H), 2.383 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 159.18, 155.25, 141.13, 133.38,
130.44, 128.43, 113.41, 55.26, 19.69.
HRMS (ESI): m/z [M + H]+ calcd for C29H22N: 384.1747; found:
384.1742.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO2: 320.1645; found:
320.1639.
2,4-Bis(3,4-dimethylphenyl)pyridine (2p)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2p
(82% yield) as an off-white solid; mp 75–77 °C.
IR (KBr): 2919.88, 1597.81, 1469.45, 814.76 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.673 (d, J = 4.8 Hz, 1 H), 7.861
(d, J = 10.4 Hz, 2 H), 7.751 (d, J = 7.6 Hz, 1 H), 7.453 (s, 1 H),
7.422 (d, J = 7.6 Hz, 1 H), 7.369–7.385 (dd, J = 5 Hz, 1.4 Hz, 1 H),
7.241 (d, J = 7.6 Hz, 2 H), 2.353 (d, J = 2.8 Hz, 6 H), 2.317 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 158.09, 149.83, 149.15, 137.68,
137.56, 137.30, 137.21, 136.92, 136.14, 130.32, 129.99, 128.17,
124.38, 124.33, 119.68, 118.21, 19.87, 19.85, 19.56, 19.52.
2,6-Bis(4-chlorophenyl)-3,5-dimethylpyridine (4d)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 4d
(60% yield) as an off-white solid; mp 140–142 °C.
IR (KBr): 3392.09, 2953.38, 1453.95, 1093.12, 830.76, 766.94
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.510 (d, J = 8.4 Hz, 4 H), 7.468
(s, 1 H), 7.400 (d, J = 8.4 Hz, 4 H), 2.356 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 154.69, 141.41, 138.92, 133.84,
130.55, 129.40, 128.29, 19.54.
HRMS (ESI): m/z [M + H]+ calcd for C19H16Cl2N: 328.0654; found:
328.0646.
HRMS (ESI): m/z [M + H]+ calcd for C21H22N: 288.1747; found:
288.1742.
2,6-Bis(3-chlorophenyl)-3,5-dimethylpyridine (4e)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 4e
(56% yield) as an off-white solid; mp 97–99 °C.
2,4-Bis(3,5-dimethylphenyl)pyridine (2q)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 2q
(70% yield) as an orange oil.
IR (neat): 2917.35, 1592.73, 1447.13, 833.72 cm–1.
IR (KBr): 3398.77, 2924.00, 1565.20, 1454.17, 1424.41, 1257.73,
1079.38, 887.55, 766.51, 704.65 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.554 (s, 2 H), 7.484 (s, 1 H),
7.423–7.448 (m, 2 H), 7.342–7.358 (m, 4 H), 2.361 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 154.53, 142.20, 141.38, 134.11,
129.73, 129.35, 129.32, 127.92, 127.33, 19.48.
HRMS (ESI): m/z [M + H]+ calcd for C19H16Cl2N: 328.0654; found:
328.0648.
1H NMR (400 MHz, CDCl3): d = 8.687 (d, J = 5.2 Hz, 1 H), 7.869
(s, 1 H), 7.652 (s, 2 H), 7.382–7.398 (dd, J = 5 Hz, 1.4 Hz, 1 H),
7.288 (s, 2 H), 7.074 (d, J = 6.4 Hz, 2 H), 2.407 (s, 12 H).
13C NMR (100 MHz, CDCl3): d = 158.27, 149.82, 149.47, 139.54,
138.65, 138.63, 138.24, 130.61, 130.58, 124.93, 124.88, 120.15,
118.84, 21.38, 21.35.
HRMS (ESI): m/z [M + H]+ calcd for C21H22N: 288.1747; found:
288.1743.
3,5-Diethyl-2,6-diphenylpyridine (4f)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 4f
(50% yield) as a yellow solid; mp 136–138 °C.
IR (KBr): 3389.84, 2967.97, 1436.79, 776.50, 698.76 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.512–7.543 (m, 5 H), 7.385–
7.422 (m, 4 H), 7.323–7.359 (m, 2 H), 2.675–2.732 (q, J = 7.6 Hz,
4 H), 1.175–1.213 (t, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 155.61, 140.82, 137.41, 135.43,
129.12, 128.03, 127.54, 25.30, 15.24.
HRMS (ESI): m/z [M + H]+ calcd for C21H22N: 288.1747; found:
288.1740.
3,5-Dimethyl-2,6-diphenylpyridine (4a)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 4a
(62%) as a purple-red solid; mp 88–90 °C.
IR (KBr): 3389.56, 2955.11, 1441.07, 700.95 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.568–7.589 (m, 4 H), 7.465 (s, 1
H), 7.398–7.434 (m, 4 H), 7.326–7.362 (m, 2 H), 2.369 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 155.79, 141.08, 140.73, 129.21,
129.07, 128.02, 127.62, 19.59.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N: 260.1434; found:
260.1430.
2,3,5,6-Tetraphenylpyridine (4g)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 4g
(55% yield) as a purple-red solid; mp 202–204 °C.
3,5-Dimethyl-2,6-di-4-tolylpyridine (4b)
Purified by flash chromatography (PE–EtOAc, 12:1) to give 4b
(70% yield) as an off-white solid; mp 79–81 °C.
Synthesis 2010, No. 24, 4228–4234 © Thieme Stuttgart · New York

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J. Liu et al.
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(13) For selected recent examples on the transition-metal-
IR (KBr): 3392.47, 3059.22, 2924.63, 1419.99, 757.70, 699.56
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.763 (s, 1 H), 7.487–7.511 (m, 4
H), 7.246–7.279 (m, 16 H).
13C NMR (100 MHz, CDCl3): d = 155.31, 141.15, 139.96, 139.71,
134.29, 130.18, 129.56, 128.35, 127.80, 127.21.
HRMS (ESI): m/z [M + H]+ calcd for C29H22N: 384.1747; found:
384.1749.
catalyzed synthesis of substituted pyridines:
(a) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J.
J. Am. Chem. Soc. 2005, 127, 5030. (b) Chang, H.-T.;
Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2007, 9, 505.
(c) Kase, K.; Goswami, A.; Ohtaki, K.; Tanabe, E.; Saino,
N.; Okamoto, S. Org. Lett. 2007, 9, 931. (d) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
3645. (e) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H.
Org. Lett. 2008, 10, 325.
(14) For selected recent examples on the synthesis of substituted
pyridines via multicomponent reactions: (a) Senaiar, R. S.;
Young, D. D.; Deiter, A. Chem. Commun. 2006, 1313.
(b) Evdokimov, N.; Magedov, I. V.; Kireev, A. S.;
Kornienko, A. Org. Lett. 2006, 8, 899. (c) Dash, J.; Lechel,
T.; Reissig, H.-U. Org. Lett. 2007, 9, 5541. (d) Ranu, B. C.;
Jana, R.; Sowmiah, S. J. Org. Chem. 2007, 72, 3152.
(e) Zhu, S.-L.; Ji, S.-J.; Su, X.-M.; Sun, C.; Liu, Y.
Tetrahedron Lett. 2008, 49, 1777. (f) Sasada, T.; Sakai, N.;
Konakahara, T. J. Org. Chem. 2008, 73, 6905.
(15) For selected recent examples on the synthesis of substituted
pyridines via using ammonium acetate as the nitrogen
source: (a) Ladouceur, G. H.; Cook, J. H.; Doherty, E. M.;
Schoen, W. R.; MacDougall, M. L.; Livingston, J. N.
Bioorg. Med. Chem. Lett. 2002, 12, 461. (b) Rodriguez, H.;
Suarez, M.; Perez, R.; Petit, A.; Loupy, A. Tetrahedron Lett.
2003, 44, 3709. (c) Bowman, M. D.; Jacobson, M. M.;
Pujanauski, B. G.; Blackwell, H. E. Tetrahedron 2006, 62,
4715. (d) Liéby-Muller, F.; Allais, C.; Constantieux, T.;
Rodriguez, J. Chem. Commun. 2008, 4207.
Acknowledgment
The authors thank the State Key Laboratory of Applied Organic
Chemistry for financial support.
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Synthesis 2010, No. 24, 4228–4234 © Thieme Stuttgart · New York