Direct ortho-arylation of N-phenacylpyridinium bromide by palladium-catalyzed C-H-bond activation

Article abstract of DOI:10.1002/chem.200901399

A novel palladium catalyzed direct ortho-arylation of N-phenacylpyridinium bromide was developed. The amazing N-phenacyl group regioselectively activates the C-H bond of pyridine and automatically departs from the arylated products. A kinetic isotope effe

Full text of DOI:10.1002/chem.200901399

FULL PAPER
DOI: 10.1002/chem.200901399
Direct ortho-Arylation of N-Phenacylpyridinium Bromide by Palladium-
À
Catalyzed C H-Bond Activation
Jimin Xu, Guolin Cheng, Deyong Su, Yantao Liu, Xinyan Wang,* and Yuefei Hu*[a]
Abstract: A novel palladium catalyzed direct ortho-arylation of N-phenacylpyridi-
nium bromide was developed. The amazing N-phenacyl group regioselectively acti-
Keywords: arylation
·
catalysis
·
·
À
vates the C H bond of pyridine and automatically departs from the arylated prod-
À
C H activation
pyridine
·
palladium
À
ucts. A kinetic isotope effect study proved that the reaction went through a C H-
bond activation pathway and 2,6-diphenylpyridine was produced stepwise from 2-
phenylpyridine.
Introduction
Ortho-arylated pyridines have found important applications
in medicinal[1] and material researches.[2] Although transi-
tion-metal-catalyzed cross-coupling reactions between or-
ganometallic electron-rich heterocycles and arylhalides have
been widely used, their application has been limited to pyri-
dine derivatives.[3,4] The reason for this is that the pyridine
ring is electron deficient and the highly effective and rela-
tively stable ortho-pyridyl organometallics have only been
presented recently.[5] However, direct arylation of heterocy-
cles has emerged as an alternative to the traditional cross-
coupling reaction in past years[6] and pioneering work on the
direct ortho-arylation of pyridine has made significant ach-
ievements.[7,8] These reactions have great attraction as pyri-
dine derivatives are used as substrates rather than the stoi-
chiometric ortho-pyridyl organometallics.
As shown in Scheme 1, two types of procedure were re-
ported based on the substrates used with either pyridines[7]
or N-substituted pyridiniums[8] (N-oxides and N-iminopyridi-
niums). The latter is more practical when using relatively
mild conditions and low-cost catalysts because the N-sub-
Scheme 1. Two types of ortho-arylation of pyridine.
À
stituent may act as an activating group for the C H-bond
activation at the ortho-position of pyridine. But, one draw-
back of those otherwise efficient procedures is that one ad-
ditional step is needed to remove the activating groups from
the target products.
Therefore, the development of desirable N-substituents as
the activating groups for highly efficient direct ortho-aryla-
tions of pyridine is greatly needed. Herein, we report the
use of N-phenacylpyridinium bromide (1a) as a substrate to
smoothly achieve a novel direct ortho-arylation of pyridine.
The amazing N-phenacyl group not only has a high ability
À
to activate the C H bond at the ortho-position of pyridine,
but also automatically departs from the arylated pyridines
after the reaction.
[a] J. Xu, G. Cheng, D. Su, Y. Liu, X. Wang, Y. Hu
Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology
(Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (P.R. China)
Fax : (+86)10-62771149.
E-mail: wangxinyan@mail.tsinghua.edu.cn
yfh@mail.tsinghua.edu.cn
Results and Discussion
It is well known that N-phenacylpyridinium halide (1) is an
essential substrate in Krçhnke pyridine synthesis, in which
the N-phenacyl group is a real reactant and the pyridine
ring plays a crucial role as an activating group (Scheme 2).[9]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901399.
Chem. Eur. J. 2009, 15, 13105 – 13110
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13105

Table 1. Effects of Pd sources on the direct ortho-arylation of 1a.[a]
Entry
Pd Sources
6a [%][b]
7a [%][b]
Total yield [%][b]
1
2
3
4
5
6
7
Pd
Pd
N
22
32
17
15
14
14
11
39
20
33
29
21
20
19
61
52
50
44
35
34
30
PdCl2 +PPh3
[Pd
[Pd
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[c]
ACHUTNGREN[NUG Pd CHTUNGTRENNUNG
[a] The mixture of 1a (1.5 mmol), 5a (1.0 mmol), Pd catalyst
(0.05 mmol), PPh3 (0.15 mmol), and K2CO3 (3 mmol) in toluene (5 mL)
was refluxed for 12 h. [b] The isolated yield was used. [c] dba: dibenzyli-
deneacetone.
Scheme 2. The Krçhnke pyridine synthesis.
The key reason for its success is that the pyridine ring can
automatically depart from the intermediate 2 by an N-alke-
nylpyridinium mechanism.
Thus, pyridinium 1 may be expected to be used as a sub-
strate in the direct ortho-arylation of pyridine. In contrast
with Krçhnke pyridine synthesis, the pyridine ring could be
used as a real reactant and the N-phenacyl group as an acti-
vating group. Therefore, in the presence of Pd catalyst, the
carbonyl group of 1 may coordinate with Pd to activate the
In the presence of PdACHTNUTRGNE(UGN OAc)2 and with PPh3 as the ligand,
the best yield of the products was produced (Table 2,
entry 1) and PCy3 gave nothing (entry 2). No catalytic activi-
ty was observed when Pd was coordinated by strong chelat-
ing ligands, such as DPPE and DPPP (entries 3 and 4),
whereas weak chelating ligand DPPF gave the desired prod-
ucts in 40% yield (entry 5).
À
C H bond at the ortho-position of pyridine. Once the aryla-
Table 2. Effects of ligands on the direct ortho-arylation of 1a.[a]
tion is finished, the carbonyl group will be enolized to form
an N-alkenylpyridinium under the basic conditions, by
which the N-phenacyl group will depart from the arylated
pyridines.
Entry
Ligands ([mol%])
6a [%][b]
7a [%][b]
Total yield [%][b]
1
2
3
4
5
PPh3 (15)
PCy3 (15)
22
0
0
0
16
39
0
0
0
24
61
0
0
0
40
DPPE (7.5)[c]
DPPP (7.5)[c]
DPPF (7.5)[c]
To prove our hypothesis, the direct ortho-arylation of N-
phenacylpyridinium bromide (1a, it is a commercially avail-
able and easily prepared crystal product.) was tested. As
shown in Scheme 3, after the mixture of 1a (1.5 equiv), bro-
[a] The mixture of 1a (1.5 mmol), 5a (1.0 mmol), PdACTHNURGTNEUNG(OAc)2 (0.05 mmol),
and K2CO3 (3 mmol) in toluene (5 mL) was refluxed for 12 h. [b] The iso-
lated yield was used. [c] DPPE: 1,2-bis(diphenylphosphino)ethane;
DPPP: 1,3-bis(diphenylphosphino)propane; DPPF: 1,1’-bis(diphenyl-
phosphino)ferrocene.
DMF, DMSO, MeCN, and PhMe were all desirable sol-
vents and gave comparable results. However, the use of
PhMe made the workup procedure more convenient. At-
tempts to improve the selectivity between 6a and 7a by
using different N-phenacyl groups, such as N-(2-methylphe-
nacyl)pyridinium bromide and N-(4-nitrophenacyl)pyridini-
um bromide, failed. However, this selectivity could be im-
proved conveniently by changing the ratio of 1a and 5a
(Table 3). When 10:1 (by molar amount) of 1a/5a was used,
the total yield was as high as 95% with monoarylated 6a as
Scheme 3. A novel direct ortho-arylation.
mobenzene (5a, 1 equiv), PdACHTNUGTRNEUNG(OAc)2 (0.05 equiv), PPh3
(0.15 equiv), and K2CO3 (3 equiv) in toluene was refluxed
overnight, two products, 2-phenylpyridine (6a) and 2,6-di-
phenylpyridine (7a), were obtained in 22 and 39% yields,
respectively. In this approach, the N-phenacyl group produ-
ces two unique results: 1) it had a high ability to activate the
Table 3. Effects of the ratio of 1a/5a on the direct ortho-arylation of
1a.[a]
À
C H bond at the ortho-position of pyridine and 2) it depart-
ed from the arylated pyridines automatically as acetophe-
none in 47% yield (since acetophenone was not chemically
stable under our conditions, some part of it may be convert-
ed to other products).
Entry
1a/5a (by mole)
6a [%][b]
7a [%][b]
Total yield [%][b]
1
2
3
4
5
1.5:1
3:1
6:1
10:1
1:4
22
46
53
64
12
39
40
37
31
50
61
86
90
95
62
Further control experiments proved that iodobenzene can
replace 5a to give the exact same result, but not chloroben-
zene. As shown in Table 1, many Pd sources can be used as
catalysts and the low-cost Pd
(entry 1).
[a] The mixture of 1a, 5a, PdACTHNUTRGNEU(GN OAc)2 (0.05 mmol), PPh3 (0.15 mmol), and
K2CO3 (3 mmol) in toluene (5 mL) was refluxed for 12 h. [b] The isolated
yield was used.
ACHTUNGRTEN(NUNG OAc)2 gave the best yield
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Direct ortho-Arylation of N-Phenacylpyridinium Bromide
FULL PAPER
a major product (entry 4). Whereas, by using a larger pro-
portion of 5a, diarylated compound 7a was produced as a
major product (entry 5).
Experiments indicated that the base was necessary for the
reaction. The scanning of different bases revealed that terti-
ary amines (NEt3, iPr2NEt) or strong bases (NaOtBu,
NaOH, Cs2CO3) could not offer any desired product 6a or
7a. However, when NaOAc, K3PO4, and K2CO3 were used
as a base, mixtures of 6a and
Scheme 4. Effects of bases on the direct ortho-arylation of 1a.
pyridines as the major products (they were separated easily)
(entries 1–8). By using the bromobenzenes with strong elec-
Table 4. The direct ortho-arylation between 1a–b and 5a–l.[a]
7a were obtained in 10, 47, and
61% yields, respectively. Based
on the conditions of the entry 2
in Table 3, control experiments
further showed that four equiv-
alents (the summation of the
amounts of 1a and 5a) of
K2CO3 gave the best total yield
(86%). However, both total
yields and selectivity were de-
creased upon reducing the
amounts of K2CO3. For exam-
ple, the total yields were ob-
tained in 71 (38:33 for 6a/7a)
and 59% (29:30 for 6a/7a) by
using three and two equivalents
of K2CO3, respectively.
We interestingly observed
that, when the reaction mixture
was treated sequentially with
NEt3 for 12 h, followed by
NaOH for 2 h, the desired
products were obtained in 27%
yield (Scheme 4). Thus, the be-
havior of these bases can be
well explained by this result:
1) the tertiary amines may be
not be strong enough to enolize
the ketone to remove the N-
phenacyl group from the target
products and 2) the strong
bases probably attack 1a quick-
ly to replace the pyridine by a
nucleophilic substitution reac-
tion before the arylation.
Entry
1
5
6
7
Yield [%][b]
86
1
1a
2
1b[c]
85
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
88
82
67
73
85
81
76
72
62
80
4
5
6
7
8
9
–
–
–
–
To generalize this novel
method, different substrates
1a–b and bromobenzenes 5a–l
were tested. As shown in
Table 4, they all gave the de-
sired products in satisfactory
yields under our optimized con-
ditions (see note of Table 4). It
is noteworthy that the chemose-
lectivity of the arylation was
also strongly influenced by bro-
mobenzenes. Normally, a mix-
10
11
12
[a] The optimized conditions: a mixture of 1 (3 mmol), 5 (1 mmol), Pd
and K2CO3 (3 mmol) in toluene (5 mL) was refluxed for 12–15 h. [b] The isolated yield was used. [c] 1b is 4-
ACHTUGNRTEN(NUGN OAc)2 (0.05 mmol), PPh3 (0.15 mmol),
ture was obtained with 2-aryl- methylpyridinium bromide.
Chem. Eur. J. 2009, 15, 13105 – 13110
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13107

Y. Hu, X. Wang et al.
tron-withdrawing or large sterically sized substituents, 2-
aryl-pyridines were obtained as single products (entries 9–
12).
than of [D4]6a. Since both 6a and [D4]6a are intermediates
for the secondary step, they continuously reacted with 5i.
Again, as a result of the kinetic isotope effect, the conver-
sion of 6a into 7a was faster than the conversion of [D4]6a
into [D3]7a. Therefore, kH/D =0.53 for 6a/[D4]6a and 3.35
for 7a/[D3]7a are the final results for a two-step reaction.
Theoretically, Pd-catalyzed direct ortho-arylation of pyri-
À
dine may proceed through three possible pathways: C H ac-
tivation, a Heck reaction, or electrophilic substitution.[10] To
clarify the pathway for our method, a kinetic isotope effect
study was performed.[11] As shown in Scheme 5, by using the
reaction of 1a/[D5]1a and 5a, values of kH/D =0.52 for 6a/
[D4]6a and 3.35 for 7a/[D3]7a were obtained, respectively,
À
This result also indicated that the C H cleavage was the ini-
tial step and 2,6-diphenylpyridine (7a) was produced step-
wise from 2-phenylpyridine (6a).
As shown in Figure 1, DFT (B3LYP/6-31G(d)) treatment
of 1a indicated that the HOMO is almost completely locat-
ed on the benzene ring (Figure 1a). However, when the ylid
1
from their H NMR spectra. These data proved that the iso-
À
topic effect occurred in this reaction and a C H-activation
pathway was suggested.
Scheme 5. The kinetic isotope effect study results of 1a/[D5]1a.
To help to understand the abnormal phenomenon of kH/
D <1.0 for 6a/[D4]6a, the kinetic isotope effect of the mono-
arylated product 2-(4-nitrophenyl)pyridine (6i) was studied.
As shown in Scheme 6, by the reaction of 1a/[D5]1a and 5i,
the normal result (kH/D =2.0) was obtained for 6i/[D4]6i.
Thus, kH/D =0.52 for 6a/[D4]6a can be well explained as
shown in Scheme 7. In the first step, the reaction of 1a pro-
ceeded faster than the reaction of [D5]1a because of the ki-
netic isotope effect, which led to the faster formation of 6a
Figure 1. DFT calculated HOMO densities at 1a and its ylids.
of 1a was produced, the pyridine ring had an extended
HOMO on its C2, C4, and C6 atoms (Figure 1b and c). This
result is in full agreement with the N-iminopyridinium ylid
(Figure 1d) and strongly implies that the ylids (Figure 1b
and c) may be the real reactants. Since no arylated product
on C4 is produced, it is suggest-
ed that the N-phenacyl group
À
may be involved in the C H-ac-
tivation steps by coordination
with Pd.
Conclusion
Scheme 6. The kinetic isotope effect of 6i/[D4]6i.
A
novel Pd-catalyzed direct
ortho-arylation of N-phenacyl-
pyridinium bromide was devel-
oped. Its unique feature is that
the activating group can depart
from the arylated pyridines au-
tomatically. A kinetic isotope
effect study proved that the re-
À
action went through a C H-
bond activation pathway. The
results from experiments and
DFT calculations indicated that
the N-phenacyl group played
two crucial roles: 1) activation
of the pyridine ring by forming
Scheme 7. A stepwise mechanism for the formation of 7a.
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Direct ortho-Arylation of N-Phenacylpyridinium Bromide
FULL PAPER
CDCl3, 258C, TMS): d=156.7, 138.8, 137.3, 136.8, 129.3, 126.8, 118.0,
21.3 ppm.
an ylid and 2) regioselective control of the arylation by coor-
dination with Pd at the ortho-position of pyridine. Further
mechanistic studies and investigations into the applications
of this methodology in organic synthesis are underway.
2-(4-Methoxyphenyl)pyridine (6d): White solid; m.p. 53–548C (EtOAc/
PE) (lit.[12] 54–558C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.63
(d, J=4.8 Hz, 1H), 7.96–7.93 (m, 2H), 7.69–7.61 (m, 2H), 7.16–7.10 (m,
1H), 6.99–6.96 ppm (m, 2H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=160.3, 156.9, 149.4, 136.5, 131.9, 128.0, 121.3, 119.6,
114.0, 55.2 ppm.
2,6-Di(4-methoxylphenyl)pyridine (7d): Yellowish solid; m.p. 185–1888C
(EtOAc/PE) (lit.[12[ 185–1868C); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=8.10 (d, J=8.2 Hz, 4H), 7.74–7.69 (m, 1H), 7.55 (d, J=7.5 Hz,
2H), 7.01 (d, J=8.2 Hz, 4H), 3.86 ppm (s, 6H); 13C NMR (75 MHz,
CDCl3, 258C, TMS): d=160.4, 156.3, 137.3, 132.3, 128.2, 117.1, 114.0,
55.3 ppm.
Experimental Section
Procedure for the test of the isotopic effect of the reaction of 1a/[D5]1a
and 5a:
1 mmol), [D5]-N-phenacylpyridinium bromide ([D5]1a, 283 mg, 1 mmol),
Pd(OAc)2 (11.2 mg, 0.05 mmol), PPh3 (39.3 mg, 0.15 mmol), and K2CO3
A mixture of N-phenacylpyridinium bromide (1a, 278 mg,
ACHTUNGTRENNUNG
2-(4-Fluorophenyl)pyridine (6e): White solid; m.p. 36–388C (EtOAc/PE)
(lit.[12] 39–40.58C); IR (KBr): n˜ =3454, 1599, 1511, 1466, 1163, 846, 779,
(552 mg, 4 mmol) in toluene (5 mL) was stirred for 5 min at room tem-
perature under nitrogen. Then, PhBr (5a, 157 mg, 1.0 mmol, 1.0 equiv)
was added and the resultant mixture was heated to reflux for 1 h. The re-
action system was then cooled to room temperature and the solid was fil-
tered off. After removal of the solvent, the crude product was purified by
chromatography (silica gel, EtOAc/PE 1:25) to give a mixture of prod-
ucts 6a/[D4]6a and 7a/[D3]7a (total 15% yield). The 1H NMR spectrum
of the mixture was determined and the value of kH/kD was calculated.
737 cmÀ1 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.66 (d, J=
;
4.5 Hz, 1H), 7.99–7.94 (m, 2H), 7.73–7.62 (m, 2H), 7.21–7.11 ppm (m,
3H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=163.4 (d, J=246.7 Hz),
156.3, 149.6, 136.7, 135.5, 128.6 (d, J=8.6 Hz), 121.9, 120.1, 115.5 ppm (d,
J=21.5 Hz); MS (EI): m/z (%): 173 (100) [M]+, 172 (68.0); elemental
analysis calcd (%) for C11H8FN: C 76.29, H 4.66, N 8.09; found: C 76.32;
H 4.64; N 8.07.
By using a similar procedure, the isotopic effect of the reaction of 1a/
[D5]1a and 5i was tested.
2,6-Di(4-fluorophenyl)pyridine (7e): White solid; m.p. 93–948C (EtOAc/
PE) (lit.[12] 94–958C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.12–
8.07 (m, 4H), 7.78–7.72 (m, 1H), 7.58 (d, J=7.5 Hz, 2H), 7.18–7.12 ppm
(m, 4H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=163.5 (d, J=
245.9 Hz), 155.7, 137.6, 135.4 (d, J=2.87 Hz), 128.7 (d, J=7.9 Hz), 118.1,
115.5 ppm (d, J=21.5 Hz).
A typical procedure for the preparation of 2-phenylpyridine (6a) and
2,6-diphenylpyridine (7a): A mixture of N-phenacylpyridinium bromide
(1a, 834 mg, 3 mmol, 3.0 equiv), PdACHTUNRGTNEUNG(OAc)2 (11.2 mg, 0.05 mmol,
0.05 equiv), PPh3 (39.3 mg, 0.15 mmol, 0.15 equiv), and K2CO3 (552 mg,
4 mmol, 4.0 equiv) in toluene (5 mL) was stirred for 5 min at room tem-
perature under nitrogen. Then, PhBr (5a, 157 mg 1.0 mmol, 1.0 equiv)
was added and the resulting mixture was heated to reflux for 12 h. The
reaction system was then cooled to room temperature and the solid was
filtered off. After removal of the solvent, the crude product was purified
by chromatography (silica gel, EtOAc/PE 1:25) to give products 6a
(71.3 mg, 46%) and 7a (46.2 mg, 40%).
2-(3-Fluorophenyl)pyridine (6 f): Yellowish oil; IR: n˜ =3071, 1583, 1567,
1472, 1454, 1423, 1285, 1190, 883, 770 cmÀ1 1H NMR (300 MHz, CDCl3,
;
258C, TMS): d=8.64 (d, J=3.8 Hz, 1H), 7.76–7.71 (m, 2H), 7.62–7.58
(m, 2H), 7.39–7.32 (m, 1H), 7.16–7.12 (m, 1H), 7.09–7.02 ppm (m, 1H);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=163.0 (d, J=243.8 Hz),
155.5, 149.4, 141.4 (d, J=7.2 Hz), 136.5, 129.9 (d, J=8.6 Hz), 122.3, 122.1
(d, J=19.4 Hz), 120.2, 115.4 (d, J=29.8 Hz), 113.5 ppm (d, J=23.0 Hz);
MS (70 eV): m/z (%): 173 (100) [M]+, 172 (55.4); elemental analysis
calcd (%) for C11H8FN: C 76.29, H 4.66, N 8.09; found: C 76.27, H 4.64,
N 8.13.
By using a similar procedure, products 6b–l and 7b–h were prepared
(Table 4).[12]
2-Phenylpyridine (6a): Colorless oil; 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=8.66–8.64 (m, 1H), 7.99–7.97 (m, 2H), 7.64–7.60 (m, 2H),
7.45–7.36 (m, 3H), 7.14–7.09 ppm (m, 1H); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=157.1, 149.4, 139.2, 136.4, 128.7, 128.5, 126.7, 121.8,
120.2 ppm.
2,6-Diphenylpyridine (7a): White solid; m.p. 79–808C (EtOAc/PE) (lit.[12]
80–818C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.12 (d, J=
7.5 Hz, 4H), 7.68–7.63 (m, 1H), 7.57 (d, J=7.2, 2H), 7.47–7.35 ppm (m,
6H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=156.6, 139.4, 137.4,
128.9, 128.6, 126.9, 118.5 ppm.
2,6-Di(3-fluorophenyl)pyridine (7 f): White solid; m.p. 71–728C (EtOAc/
PE); IR: n˜ =3418, 1579, 1567, 1459, 1264, 1192, 784, 691 cmÀ1 1H NMR
;
(300 MHz, CDCl3, 258C, TMS): d=7.79 (d, J=10.3 Hz, 2H), 7.71 (d, J=
7.6 Hz, 2H), 7.62–7.56 (m, 1H), 7.40–7.37 (m, 2H), 7.32–7.24 (m, 2H),
7.04–6.98 ppm (m, 2H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
163.1 (d, J=243.1 Hz), 154.8, 141.2 (d, J=7.2 Hz), 137.4, 129.9 (d, J=
7.9 Hz), 122.1 (d, J=8.6 Hz), 118.7, 115.6 (d, J=20.8 Hz), 113.5 ppm (d,
J=22.9 Hz); MS (70 eV): m/z (%): 267 (100) [M]+, 266 (41); elemental
analysis calcd (%) for C17H11F2N: C 76.39, H 4.15, N 5.24; found: C
76.41, H 4.17, N 5.22.
2-(2-Methylphenyl)pyridine (6g): Yellowish oil; 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=8.68–8.66 (m, 1H), 7.71–7.64 (m, 1H), 7.40–7.34
(m, 2H), 7.26–7.23 (m, 3H), 7.20–7.15 (m, 1H), 2.35 ppm (s, 3H);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=160.0, 149.1, 140.4, 136.0,
135.7, 130.7, 129.5, 128.2, 125.8, 124.0, 121.5, 20.2 ppm.
4-Methyl-2-phenylpyridine (6b): Yellow solid; m.p. 47–488C (EtOAc/PE)
(lit.12 <508C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.54 (d, J=
5.1 Hz, 1H), 7.97 (d, J=7.2 Hz, 2H), 7.52 (s, 1H), 7.48–7.38 (m, 3H),
7.03 ppm (d, J=4.8 Hz, 1H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=157.2, 149.3, 147.6, 139.4, 128.7, 128.6, 126.8, 123.0,
121.4, 21.1 ppm.
2,6-Di(2-methylphenyl)pyridine (7g): White solid; m.p. 66–688C (EtOAc/
PE) (lit.[12] 68–708C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.76
(t, J=7.8 Hz, 1H), 7.45–7.42 (m, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.27–7.22
(m, 6H), 2.42 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
159.4, 140.6, 136.2, 135.7, 130.6, 129.8, 128.1, 125.7, 121.9, 20.5 ppm.
4-Methyl-2,6-diphenylpyridine (7b): Yellow solid; m.p. 71–728C (EtOAc/
PE) (lit.[12] 72–738C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.11
(d, J=7.2 Hz, 4H), 7.47–7.42 (m, 6H), 7.39–7.35 (m, 2H), 2.36 ppm (s,
3H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=156.6, 148.2, 139.5,
128.7, 128.5, 126.9, 119.6, 21.3 ppm.
2-(2-Methoxylphenyl)pyridine (6h): Colorless oil; 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=8.65 (dd, J=4.8, 1.0 Hz, 1H), 7.82–7.75 (m, 2H),
7.55 (dt, J=7.5, 1.5 Hz, 1H), 7.31–7.25 (m, 1H), 7.06–7.01 (m, 2H), 6.88
(d, J=8.3 Hz, 1H), 3.68 ppm (s, 3H); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=156.3, 155.4, 148.7, 135.0, 130.5, 129.4, 128.4, 124.5, 121.0,
120.3, 110.7, 54.8 ppm.
2-(4-Methylphenyl)pyridine (6c): Colorless oil; 1H NMR: d=8.63 (d, J=
1.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.60–7.56 (m, 2H), 7.22 (d, J=
8.2 Hz, 2H), 7.08–7.04 (m, 1H), 2.33 ppm (s, 3H); 13C NMR: d=157.0,
149.2, 138.5, 136.3, 129.1, 126.4, 121.4, 119.8, 20.9 ppm.
2,6-Di(4-methylphenyl)pyridine (7c): White solid; m.p. 163–1658C
(EtOAc/PE) (lit.[12] 165–1668C); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=8.04 (d, J=8.3 Hz, 4H), 7.76–7.71 (m, 1H), 7.61 (d, J=7.2 Hz,
2H), 7.28 (d, J=7.9 Hz, 4H), 2.41 ppm (s, 6H); 13C NMR (75 MHz,
2,6-Di(2-methoxylphenyl)pyridine (7h): Yellowish solid; m.p. 118–1208C
(EtOAc/PE) (lit.[12] 1178C); 1H NMR (300 MHz, CDCl3, 258C, TMS):
Chem. Eur. J. 2009, 15, 13105 – 13110
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Y. Hu, X. Wang et al.
d=7.93 (dd, J=7.7, 1.4 Hz, 2H), 7.79–7.67 (m, 3H), 7.38–7.31 (m, 2H),
7.07 (t, J=7.5 Hz, 2H), 6.98 (d, J=8.3 Hz, 2H), 3.84 ppm (s, 6H);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=157.0, 155.3, 135.1, 131.4,
129.6, 129.5, 123.0, 121.0, 111.3, 55.6 ppm.
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1584–1586; Angew. Chem. Int. Ed. 2001, 40, 1536–1538.
2-(4-Nitrophenyl)pyridine (6i): Yellowish solid; m.p. 129–1308C (EtOAc/
PE) (lit.[12] 130–1318C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
8.75 (d, J=4.8 Hz, 1H), 8.33–8.30 (m, 2H), 8.19–8.16 (m, 2H), 7.84–7.81
(m, 2H), 7.37–7.32 ppm (m, 1H); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=154.7, 150.1, 148.1, 145.2, 137.1, 127.6, 123.9, 123.5, 121.2 ppm.
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4776; Angew. Chem. Int. Ed. 2008, 47, 4695–4698.
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107, 174–238; b) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007,
36, 1173–1193; c) L.-C. Campeau, K. Fagnou, Chem. Commun.
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D. E. Ponde, Y. Sasson, J. Chem. Soc. Perkin Trans. 2 2000, 1809–
1812.
Methyl 4-(2-pyridyl)benzoate (6j): Yellowish solid; m.p. 98–998C
(EtOAc/PE) (lit.[3] 99–1008C); 1H NMR (300 MHz, CDCl3, 258C, TMS):
d=8.68 (d, J=4.5 Hz, 1H), 8.11 (d, J=8.6 Hz, 2H), 8.04 (d, J=8.3 Hz,
2H), 7.70–7.66 (m, 2H), 7.24–7.18 (m, 1H), 3.89 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3, 258C, TMS): d=166.5, 155.7, 149.5, 143.2, 136.6, 130.0,
129.7, 126.5, 122.6, 120.6, 51.8 ppm.
2,2’-Bipyridine (6k): White solid; m.p. 68–708C (EtOAc/PE) (lit.[12]
728C); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.69 (d, J=4.1 Hz,
2H), 8.40 (dd, J=7.2, 1.0 Hz, 2H), 7.81 (dt, J=7.6, 1.7 Hz, 2H), 7.33–
7.28 ppm (m, 2H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=155.9,
149.0, 136.7, 123.5, 120.9 ppm.
2-(1-Naphathyl)pyridine (3l): Yellow oil; 1H NMR (300 MHz, CDCl3,
258C, TMS): d=8.79 (d, J=4.1 Hz, 1H), 8.10–8.07 (m, 1H), 7.90 (d, J=
8.2 Hz, 2H), 7.80 (dt, J=7.5, 1.0 Hz, 1H), 7.61–7.36 (m, 3H), 7.51–7.46
(m, 2H), 7.33–7.29 ppm (m, 1H); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=159.2, 149.5, 138.4, 136.3, 133.9, 131.1, 128.8, 128.3, 127.4,
126.4, 125.8, 125.5, 125.2, 125.0, 122.0 ppm.
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Acknowledgements
This work was supported by NNSFC (20672066, 30600779) and by
CFKSTP from the Ministry of Education of China (0706003).
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[12] With the exception of 6 f and 7 f, all other products are known com-
pounds and the cited references for their physical data can be found
in the Supporting Information.
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Received: May 26, 2009
Published online: October 23, 2009
13110
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 13105 – 13110