Modified palladium-catalyzed regioselective ortho-arylation of sp2 C-H bond substrates with a low catalyst loading

Article abstract of DOI:10.1016/j.tet.2008.11.001

A novel and generally applicable system for ortho-arylation of a broad range of sp² C-H bond substrates such as arylated benzoxazoles, acylated anilines, and pyridines has been developed. The arylation was performed in trifluoroacetic acid (TFA

Full text of DOI:10.1016/j.tet.2008.11.001

Tetrahedron 65 (2009) 914–919
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Modified palladium-catalyzed regioselective ortho-arylation of sp2 C–H bond
substrates with a low catalyst loading
*
Fan Yang, Yangjie Wu , Yanan Li, Biao Wang, Junli Zhang
Department of Chemistry, Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Key Laboratory of Applied Chemistry of Henan Universities,
Zhengzhou University, Zhengzhou 450052, PR China
a r t i c l e i n f o
a b s t r a c t
A novel and generally applicable system for ortho-arylation of a broad range of sp2 C–H bond substrates
such as arylated benzoxazoles, acylated anilines, and pyridines has been developed. The arylation was
performed in trifluoroacetic acid (TFA) under air by using PdCl2 as the catalyst with a low catalyst loading
of 1 mol %. And it was found for the first time that the addition of weak base K3PO4 to the acidic solvent
could remarkably enhance the reaction rate. The arylated products were isolated in moderate to good
yields with high regioselectivity for the substrates containing a meta-substituent. This arylation is
tolerant with various functional groups such as CH3, CH3O, CH3CO, Br, and Cl.
Article history:
Received 30 August 2008
Received in revised form 29 October 2008
Accepted 4 November 2008
Available online 7 November 2008
Keywords:
Palladium catalysis
Weak bases
Arylation
Ó 2008 Elsevier Ltd. All rights reserved.
C–H activation
1. Introduction
co-workers showed that acetamine could direct highly regio- and
chemo-selective ortho-arylation of acetanilides with trialkoxyaryl-
Transition-metal-catalyzed C–C and C–heteroatom bond for-
mations via cleavage of C–H bonds are recently increasingly
becoming facile and reliable protocols in organic synthesis due to
their potential shortening of synthetic steps.1 As a result, the de-
velopment of such C–H activation would act as an attractive alter-
native to the traditional carbon–carbon couplings (such as Suzuki,
Stille, and Negishi reaction) and thereby emerge as a fascinating
area rich in opportunities and challenges.2 To date, direct func-
tionalization of C–H bond under palladium, ruthenium, or rhodium
catalysis has been realized in arenes with a directing-group (such as
the pyridine, imine, acetamine, carboxylic acid, and oxazoline)3 and
even certain free heterocycles.4
silanes through C–H functionalization.3c Recently, we have also
reported Pd(OAc)2-mediated benzoxazole directing regioselective
ortho-arylation by coupling with aryl iodides using AgOAc as the
additive for iodide removal.6 However, the reported systems mostly
employed Pd(OAc)2 as the palladium source under the catalyst
loadings of 5 mol % or even higher. Therefore, the more efficient
catalytic system (such as lower catalyst loadings, new catalyst
species, new additives) for such C–H activation is to be explored.
On the other hand, the utilized reaction conditions for func-
tionalization of C–H bond are two different types of catalytic
systems (ligand/base/aprotic polar solvent and additive/acidic
solvent).3,4 But what happens when a weak base is added to the
acidic catalytic system? The question prompted us to investigate
catalytic characteristics of the novel system involving a weak base
and an additive in acidic solvent. Herein, we disclose that a low
catalyst loading (1 mol %) of PdCl2 is sufficient and generally
applicable for the direct arylation of a wide range of sp2 C–H bond
substrates (e.g., arylated benzoxazole, acylated anilines, and pyri-
dines), and discover for the first time that the weak bases enhance
the reactivity greatly in trifluoroacetic acid (TFA).
Compared to sp3 C–H bonds, many efforts have been devoted
to activate aromatic sp2 C–H bonds, since the unsaturated aryl
motif is a predominant feature in many pharmaceutically relevant
and biologically active compounds.4a,5 In particular, palladium-
promoted regioselective direct arylation of sp2 ortho-C–H bond
has received the most attention. Sanford and co-workers have
focused on the arylation of 2-arylpyridines and other nitrogen
heterocycles with diphenyliodonium salts in AcOH or AcOH/Ac2O
using 5 mol % of Pd(OAc)2 as the catalyst.3a Subsequently, Daugulis
and co-workers have demonstrated the Pd(OAc)2-catalyzed direct
arylation of benzoic acids in two different systems (AgOAc/HOAc
and alkylphosphine ligand/Cs2CO3/DMF).3b In addition, Shi and
2. Results and discussion
Under the base-free conditions, the arylation of 2-(3-methyl
phenyl) benzoxazole (1a) with iodobenzene (2a) catalyzed by
1 mol % of PdCl2 was explored and only a very low GC yield was
* Corresponding author. Tel./fax: þ86 371 67766667.
E-mail address: wyj@zzu.edu.cn (Y. Wu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.001

F. Yang et al. / Tetrahedron 65 (2009) 914–919
915
Table 2
observed (Table 1, entry 1). However, gratifyingly, the addition of
PdCl2-catalyzed ortho-arylation of 2-arylbenzoxazoles via C–H activationa
2 equiv of KOAc to trifluoroacetic acid (TFA) solution produced 3a in
35% GC yield (Table 1, entry 2). It indicated that the reactivity would
be also dependent on other factors and the results for the screening
of the reaction conditions with respect to bases and palladium
sources are shown in Table 1. Under the catalyst loading of 1 mol %,
various weak bases (such as NaOAc, KF$2H2O, K2HPO4, CsF, and
K3PO4) were examined in the arylation, and moderate to excellent
yields were obtained (Table 1, entries 3–7). Notably, K3PO4 was
shown to be the base of the best choice to give 3a in the GC yield of
95% (Table 1, entry 7). However, when the loading of K3PO4 was
decreased from 2 equiv (0.50 mmol) to 1.5 equiv (0.375 mmol), the
reaction gave a moderate GC yield of 82% (Table 1, entry 8). Several
other palladium species were checked for the arylation of 1a with
2a. Pd(OAc)2 as the catalyst was also effective affording 3a in 85%
GC yield (Table 1, entry 9). Other palladium catalysts, PdCl2(PPh3)2
and PdCl2(PhCN)2 provided 3a in 72% and 54% GC yields, re-
spectively (Table 1, entries 10–11).
Under the above optimized conditions, the scope of the diverse
sp2 C–H bond substrates and substituted aryl iodides was in-
vestigated. Initially, arylation of 2-arylbenzoxazoles were probed
and the results are outlined in Table 2. The arylation could tolerate
various functional groups such as CH3O, Br, Cl, and CH3CO. This
would permit construction of more complicated structures
through conventional Pd(0)/Pd(II) coupling processes. The elec-
tronic factor had a critical effect on the arylation. Electron-donating
substituents would enhance the reactivity, while electron-
withdrawing substituents would reduce the rate of the arylation
(Table 2, entries 1–5). However, the reactions of aryl iodides
bearing an ortho-substituent (either electron-donating or electron-
withdrawing group) did not give the satisfactory results due to the
ortho-effect (Table 2, entries 6 and 7). Even for the iodide
containing an electron-donating substituent (CH3), the arylated
product could not be observed (Table 2, entry 6). The arylation of
iodobenzene (2a) with 2-arylbenzoxazoles containing several
functional groups was examined and moderate to good yields were
obtained (Table 2, entries 8–11).
Ar
O
N
O
N
PdCl2, AgOAc
K3PO4, TFA, Reflux
+
ArI
R
R
2
1
3
Entry R (1)
Ar (2)
Product
Time Yieldb
(h) (%)
1
3-Me (1a)
4-Me-C6H4 (2b)
40
91 (3b)
O
N
OCH3
2
3
1a
1a
3-MeO-C6H4 (2c)
3-Me-C6H4 (2d)
100 90 (3c)
O
N
64
96
92 (3d)
84 (3e)
O
N
Br
4
5
1a
1a
3-Br-C6H4 (2e)
O
N
COCH3
4-MeCO-C6H4 (2f)
96
25 (3f)
O
N
6
7
1a
1a
2-Me-C6H4 (2g)
2-Cl-C6H4 (2h)
d
d
d
d
d
d
Subsequently, the catalytic protocol also allowed for efficient
arylation of acylated anilines (Table 3). The arylation showed highly
regioselectivity for acylated anilines containing a meta-substituent.
The arylation of N-(3-methyl phenyl)-3,3-dimethylbutanamide (4a)
with a series of aryl iodides proceeded smoothly to afford
8
H (1b)
C6H5 (2a)
53
60 (3g)
O
N
Table 1
Effect of bases and catalysts on the ortho-arylation of 2-(3-methyl phenyl) ben-
zoxazole (1a) with iodobenzene (2a)a
Ph
O
N
9
3-Br (1c)
2a
120 82 (3h)
O
N
O
N
Pd-cat, AgOAc
Base, TFA, Reflux
+
PhI
Br
2a
1a
3a
Entry
Catalyst
Base
Yieldb (%)
O
N
10
11
3-Cl (1d)
2a
110 87 (3i)
1
2
3
4
5
6
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(PhCN)2
d
9
35
24
53
39
44
95 (88)
82 (70)
85 (72)
72
KOAc
NaOAc
KF$2H2O
K2HPO4
CsF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cl
7
8c
9
O
N
3,4-MeO (1e) 2a
120 72 (3j)
H3CO
10
11
H3CO
54
a
a
All the reactions were carried out in the presence of
1
(0.25 mmol), 2
All the reactions were carried out in the presence of 1a (0.25 mmol), 2a
(0.75 mmol), AgOAc (0.75 mmol), base (0.50 mmol), and catalyst (0.0025 mmol,
1 mol %) in TFA (0.6 mL) under reflux for 30 h.
(0.75 mmol), AgOAc (0.75 mmol), K3PO4 (0.50 mmol), and PdCl2 (0.0025 mmol,
1 mol %) in TFA (0.6 mL) under reflux.
b
b
Yields are given for isolated products.
GC yield (isolated yield) based on the amount of 1a.
K3PO4 (0.375 mmol) was used.
c

916
F. Yang et al. / Tetrahedron 65 (2009) 914–919
corresponding products in moderate to good yields (Table 3, entries
1–5). The ortho-effect also had great influence for the iodide bearing
ortho-substituent (2g) and the arylation did not occur (Table 3, entry
6). In the case of a moderate electron-withdrawing group (Cl)
substituted acylated aniline (4b), the desired products were also
obtained in moderate to good yields after a prolonged time (Table 3,
entries 7–11). Results for the reaction of N-(2-methyl phenyl)-3,3-
dimethylbutanamide (4c) with several aryl iodides were similar to
those of 4a and good yields were observed (Table 3, entries 12–14).
In addition, the catalytic system was successfully applied to
arylation of 2-arylpyridine (Table 4). The reactions of 2-phenyl-
prydine with several aryl iodides were carried out efficiently and
diarylated products were obtained in moderate to good yields
(Table 4, entries 1–5). Functional groups such as CH3O and Br could
be tolerated in the arylation. However, for ortho-substituted iodide,
even containing an electron-donating group (CH3), the product was
not observed (Table 4, entry 6).
Table 3
PdCl2-catalyzed ortho-arylation of acylated anilines via C–H activationa
Ar
PdCl2, AgOAc
K3PO4, TFA, 90 °C
NHCOR'
+
ArI
NHCOR'
R' = CH2
R
R
4
2
CMe3
5
Entry R (4)
Ar (2)
Product
Time Yieldb
(h)
18
(%)
R'COHN
1
2
3
3-Me (4a) C6H5 (2a)
90 (5a)
R'COHN
R'COHN
4a
4a
4a
4-Me-C6H4 (2b)
50
45
82 (5b)
87 (5c)
3. Conclusion
3-MeO-C6H4 (2c)
3-Me-C6H4 (2d)
OMe
In summary, we have developed an efficient system for the di-
rect arylation of several sp2 C–H bond substrates such as arylated
benzoxazole, acylated anilines, and pyridines through C–H activa-
tion process. Remarkable features of the arylation are high effi-
ciency using PdCl2 as the catalyst with a low loading of 1 mol %, the
arylated regioselectivity of the less sterically hindered ortho-C–H
bond, and the unexpected enhancement of the arylation rate that
the base K3PO4 displays in an acidic solvent (TFA). The reaction can
be compatible to several functional groups such as CH3, CH3O, and
CH3CO, as well as Br and Cl substituents, which would permit to be
functionalized further to construct more complicated structures.
The arylation of iodides bearing ortho-substituent did not occur due
to the ortho-effect. Current efforts are focused on the mechanistic
studies and synthetic application of this efficient methodology.
R'COHN
R'COHN
4
5
35
88
82 (5d)
80 (5e)
4a
4a
3-Br-C6H4 (2e)
2-Me-C6H4 (2g)
Br
6
7
d
d
d
R'COHN
3-Cl (4b) 2a
60
69 (5f)
Cl
R'COHN
4. Experimental
8
4b
4b
4b
4b
2b
2c
2d
2e
120
125
58
66 (5g)
86 (5h)
67 (5i)
60 (5j)
85 (5k)
86 (5l)
4.1. General methods
Cl
R'COHN
1H and 13C NMR spectra were recorded on a Bruker DPX-400
spectrometer with CDCl3 as the solvent and TMS as an internal
standard. Melting points were measured using a WC-1 microscopic
apparatus and are uncorrected. GC analysis was performed on
Agilent 4890D gas chromatograph. Mass spectra were measured on
an LC-MSD-Trap-XCT instrument. High-resolution mass spectra
were measured on a Waters Q-Tof MicroTM spectrometer. 2-Aryl-
benzoxazoles (1),7 AgOAc,8 and acylated anilines (4)9 were pre-
pared by following the previously published procedures. CH2Cl2
(analytical grade) was stored over molecular sieves and used
without further purification. Ethyl acetate and hexane (analytical
grade) were used for column chromatography without purification.
The other chemicals were bought from commercial sources and
used as received unless otherwise noted.
9
OMe
Cl
R'COHN
10
11
12
13
Cl
R'COHN
100
32
Br
Cl
R'COHN
2-Me (4c) 2a
R'COHN
R'COHN
4c
4c
2b
2d
29
4.2. General procedure for arylation of C–H bond
Substrate (0.25 mmol), aryl iodide (0.75 mmol), PdCl2
(0.0025 mmol, 1 mol %), K3PO4 (0.50 mmol), and silver acetate
(0.75 mmol) were dissolved in trifluoroacetic acid (0.6 mL) in a 5 mL
vial under air and heated at a specific temperature. The reaction
process was monitored by GC analysis. After the reaction was
complete, the mixture was diluted with CH2Cl2 (10 mL), filtered
through a pad of Celite, and washed multiple times with CH2Cl2. The
combined organic solutions were evaporated under reduced pres-
sure and the residue was purified by flash chromatography on silica
gel (ethyl acetate/hexane) to give the pure product.
14
48
81 (5m)
a
All the reactions were carried out in the presence of
4 (0.25 mmol), 2
(0.75 mmol), AgOAc (0.75 mmol), K3PO4 (0.50 mmol), and PdCl2 (0.0025 mmol,
1 mol %) in TFA (0.6 mL) at 90 ꢀC.
b
Yields are given for isolated products.

F. Yang et al. / Tetrahedron 65 (2009) 914–919
917
Table 4
4.2.4. 2-[2-(3-Methyl phenyl)-5-methyl phenyl]benzoxazole (3d)
White solid, mp 101–102 ꢀC; 1H NMR (400 MHz, CDCl3):
2.29
PdCl2-catalyzed ortho-arylation of 2-phenylpyridine via C–H activationa
d
Ar
(s, 3H), 2.45 (s, 3H), 7.00 (d, J¼7.02 Hz, 1H), 7.05–7.20 (m, 3H),
PdCl2, AgOAc
K3PO4, TFA, Reflux
7.21–7.28 (m, 3H), 7.32–7.36 (m, 2H), 7.72 (d, J¼7.68 Hz, 1H), 7.93
+
ArI
(s, 1H); 13C NMR (100 MHz, CDCl3):
d 21.02, 21.54, 110.60, 120.05,
N
N
124.34, 124.91, 125.98, 126.11, 127.91, 127.97, 129.54, 131.18, 131.51,
131.90, 137.38, 137.72, 139.79, 140.85, 141.74, 150.79, 164.29; HRMS
(positive ESI) calcd for C21H17NO: 300.1388 (MþþH); found:
300.1390.
Ar
7
6
2
Entry
1
Ar (2)
Product
Time (h)
75
Yieldb (%)
4.2.5. 2-[2-(3-Bromo phenyl)-5-methyl phenyl]benzoxazole (3e)6
N
Light yellow oil; 1H NMR (400 MHz, CDCl3):
d 2.46 (s, 3H), 7.08–
C6H5 (2a)
78 (7a)
7.15 (m, 2H), 7.23–7.31 (m, 4H), 7.35–7.40 (m,1H), 7.40–7.46 (m,1H),
7.49–7.53 (m, 1H), 7.67–7.73 (m, 1H), 7.98 (s, 1H); 13C NMR
(100 MHz, CDCl3):
d 21.01, 110.56, 120.10, 122.09, 124.45, 125.08,
125.84, 127.77, 129.43, 130.13, 131.08, 131.44, 131.84, 131.93, 138.00,
138.11, 141.60, 143.09, 150.68, 163.50.
N
2
3
4
5
4-Me-C6H4 (2b)
3-MeO-C6H4 (2c)
3-Me-C6H4 (2d)
45
76
72
75 (7b)
74 (7c)
72 (7d)
4.2.6. 2-[2-(4-Acetyl phenyl)-5-methyl phenyl]benzoxazole (3f)6
White solid, mp 169–172 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.50
OMe
OMe
(s, 3H), 2.61 (s, 3H), 7.26–7.32 (m, 3H), 7.32–7.39 (m, 3H), 7.39–7.44
N
(m, 1H), 7.70 (d, J¼7.80 Hz, 1H), 7.91 (d, J¼7.80 Hz, 2H), 7.98 (s, 1H);
13C NMR (100 MHz, CDCl3):
d 20.98, 26.64, 110.54, 120.09, 124.44,
125.07, 125.84, 128.18, 129.13, 130.92, 131.52, 131.92, 135.68, 138.31,
138.36, 141.54, 145.97, 150.62, 163.45, 197.88.
N
4.2.7. 2-(2-Phenyl phenyl)benzoxazole (3g)6
Light yellow oil; 1H NMR (400 MHz, CDCl3):
d 7.15–7.35 (m, 8H),
7.45–7.51 (m, 2H), 7.51–7.59 (m, 1H), 7.70 (d, J¼7.60 Hz, 1H), 8.11
(dd, J¼7.30, 1.80 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 110.58,
Br
Br
120.13, 124.37, 124.97, 126.33, 127.32, 127.59, 128.18, 128.86, 131.04,
131.20, 141.02, 141.74, 142.50, 150.77, 163.91.
N
3-Br-C6H4 (2e)
2-Me-C6H4 (2g)
95
54 (7e)
4.2.8. 2-(2-Phenyl-5-bromo phenyl)benzoxazole (3h)6
White solid, mp 113–115 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.22–
6
d
d
d
7.29 (m, 4H), 7.29–7.38 (m, 5H), 7.67–7.74 (m, 2H), 8.29 (d,
a
All the reactions were carried out in the presence of 2-phenylpyridine
(0.25 mmol), 2 (0.75 mmol), AgOAc (0.75 mmol), K3PO4 (0.50 mmol), and PdCl2
(0.0025 mmol, 1 mol %) in TFA (0.6 mL) under reflux.
6
J¼2.04 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 110.59, 120.23, 121.45,
124.51, 125.28, 127.59, 127.89, 128.21, 128.65, 132.69, 133.53, 133.87,
139.84, 141.26, 141.45, 150.68, 162.26.
b
Yields are given for isolated products.
4.2.9. 2-(2-Phenyl-5-chloro phenyl)benzoxazole (3i)6
4.2.1. 2-(2-Phenyl-5-methyl phenyl)benzoxazole (3a)6
White solid, mp 88–90 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.22–
White solid, mp 62–64 ꢀC; 1H NMR (400 MHz, CDCl3):
d
2.46 (s,
3H), 7.22–7.31 (m, 8H), 7.36–7.38 (m, 2H), 7.71 (d, J¼8.00 Hz, 1H),
7.94 (s, 1H); 13C NMR (100 MHz, CDCl3):
19.88, 109.49, 118.90,
7.28 (m, 4H), 7.28–7.35 (m, 4H), 7.39–7.43 (m, 1H), 7.54 (dd, J¼8.00,
2.16 Hz,1H), 7.71 (d, J¼7.32 Hz,1H), 8.14 (d, J¼2.16 Hz,1H); 13C NMR
d
(100 MHz, CDCl3):
d 110.59, 120.23, 124.52, 125.28, 127.57, 127.61,
123.29, 123.85, 124.80, 126.03, 127.03, 127.78, 130.07, 130.39, 130.85,
136.41, 138.61, 139.84, 140.45, 149.63, 163.11.
128.19, 128.72, 130.66, 130.94, 132.49, 133.62, 139.83, 140.82, 141.43,
150.68, 162.39.
4.2.2. 2-[2-(4-Methyl phenyl)-5-methyl phenyl]benzoxazole (3b)6
4.2.10. 2-(2-Phenyl-4,5-dimethoxyl phenyl)benzoxazole (3j)6
White solid, mp 111–114 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.34
White solid, mp 129–132 ꢀC; 1H NMR (400 MHz, CDCl3):
d 3.97
(s, 3H), 2.45 (s, 3H), 7.07–7.12 (m, 2H), 7.12–7.18 (m, 2H), 7.20–7.31
(s, 3H), 4.02 (s, 3H), 6.93 (s, 1H), 7.20–7.24 (m, 2H), 7.27–7.31 (m,
(m, 3H), 7.31–7.37 (m, 2H), 7.68–7.74 (m, 1H), 7.91 (s, 1H); 13C NMR
3H), 7.32–7.36 (m, 3H), 7.67 (s, 1H), 7.68–7.72 (m, 1H); 13C NMR
(100 MHz, CDCl3):
d 20.95, 21.22, 110.61, 120.04, 124.29, 124.84,
(100 MHz, CDCl3):
d 56.09, 56.25, 110.39, 113.01, 113.83, 118.13,
125.95, 128.72, 128.87, 131.17, 131.56, 131.88, 136.76, 137.21, 137.95,
139.64, 141.73, 150.78, 164.32.
119.66, 124.25, 124.61, 127.12, 128.04, 128.94, 136.20, 141.09, 141.58,
148.24, 150.59, 150.92, 163.90.
4.2.3. 2-[2-(3-Methoxyl phenyl)-5-methyl phenyl]-
4.2.11. N-(2-Phenyl-5-methyl phenyl)-3,3-dimethyl-
benzoxazole (3c)6
butanamide (5a)
White solid, mp 169–172 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.46
White solid, mp 99–100 ꢀC; 1H NMR (400 MHz, CDCl3):
d 0.98 (s,
(s, 3H), 3.66 (s, 3H), 6.80–6.91 (m, 3H), 7.14–7.23 (m, 1H), 7.23–
9H), 2.03 (s, 2H), 2.40 (s, 3H), 6.98 (d, J¼7.70 Hz, 1H), 7.06 (s, 1H),
7.32 (m, 3H), 7.35–7.40 (m, 2H), 7.16 (dd, J¼7.60, 1.84 Hz, 1H), 7.91
7.12 (d, J¼7.70 Hz, 1H), 7.31–7.36 (m, 2H), 7.38–7.42 (m, 1H), 7.43–
(s, 1H); 13C NMR (100 MHz, CDCl3):
d 20.97, 55.17, 110.58, 113.05,
7.49 (2H), 8.19 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 21.47, 29.68,
114.16, 120.00, 121.46, 124.33, 124.92, 126.04, 129.08, 130.97,
131.44, 131.85, 137.57, 139.46, 141.66, 142.28, 150.78, 159.35,
164.12.
31.21, 51.86, 121.61, 124.83, 127.78, 128.98, 129.24, 129.37, 129.73,
134.58, 138.17, 138.44, 169.97; HRMS (positive ESI) calcd for
C19H23NO: 304.1677 (MþþNa); found: 304.1618.

918
F. Yang et al. / Tetrahedron 65 (2009) 914–919
4.2.12. N-[2-(4-Methyl phenyl)-5-methyl phenyl]-3,3-
dimethylbutanamide (5b)
4.2.19. N-[2-(3-Methyl phenyl)-5-chloro phenyl]-3,3-
dimethylbutanamide (5i)
White solid, mp 67–69 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.90 (s,
White solid, mp 46–49 ꢀC; 1H NMR (400 MHz, CDCl3):
d 0.99 (s,
9H), 1.94 (s, 2H), 2.29 (s, 3H), 2.32 (s, 3H), 6.86 (d, J¼7.54 Hz, 1H),
9H), 2.03 (s, 2H), 2.40 (s, 3H), 7.07–7.15 (m, 5H), 7.22–7.27 (m, 1H),
6.98–7.04 (m, 2H), 7.15 (m, 4H), 8.08 (s, 1H), 13C NMR (100 MHz,
7.34–7.40 (m, 1H), 8.49 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
21.39,
CDCl3):
d
21.13, 21.39, 29.65, 31.17, 51.73, 121.51, 124.76, 129.15,
29.66, 31.26, 51.90, 120.51, 123.78, 126.14, 129.06, 129.08, 129.90,
129.98, 130.66, 133.92, 135.86, 136.93, 139.03, 169.92; HRMS
(positive ESI) calcd for C19H22ClNO: 338.1288 (MþþNa); found:
338.1257.
129.61, 129.74, 134.59, 135.06, 137.48, 138.10, 169.93; HRMS
(positive ESI) calcd for C20H25NO: 318.1834 (MþþNa); found:
318.1820.
4.2.13. N-[2-(3-Methoxyl phenyl)-5-methyl phenyl]-3,3-
4.2.20. N-[2-(3-Bromo phenyl)-5-chloro phenyl]-3,3-
dimethylbutanamide (5c)
dimethylbutanamide (5j)
White solid, mp 70–72 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.91 (s,
White solid, mp 98–100 ꢀC; 1H NMR (400 MHz, CDCl3):
d 1.01 (s,
9H), 1.96 (s, 2H), 2.32 (s, 3H), 3.74 (s, 3H), 6.77–6.92 (m, 4H), 7.04 (d,
9H), 2.06 (s, 2H), 7.00 (s, 1H), 7.12–7.14 (m, 2H), 7.24–7.28 (m, 1H),
J¼7.74 Hz, 2H), 7.26–7.32 (m, 1H), 8.13 (s, 1H); 13C NMR (100 MHz,
7.33–7.39 (m, 1H), 7.47–7.50 (m, 1H), 7.57 (d, J¼7.84 Hz, 1H), 8.41 (s,
CDCl3):
d
21.45, 29.66, 31.17, 51.85, 55.24, 113.38, 114.85, 121.43,
1H); 13C NMR (100 MHz, CDCl3):
d 29.68, 31.30, 51.75,121.32,123.21,
121.47, 124.68, 129.00,129.54, 129.95, 134.59, 138.45, 139.53,159.98,
169.93; HRMS (positive ESI) calcd for C20H25NO2: 334.1783
(MþþNa); found: 334.1765.
124.23, 127.83, 128.69, 130.67, 131.42, 132.22, 134.62, 135.66, 139.16,
170.04; HRMS (positive ESI) calcd for C18H19BrClNO: 402.0236
(MþþNa); found: 402.0224.
4.2.14. N-[2-(3-Methyl phenyl)-5-methyl phenyl]-3,3-
4.2.21. N-(2-Phenyl-6-methyl phenyl)-3,3-dimethyl-
dimethylbutanamide (5d)
butanamide (5k)
White solid, mp 74–77 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.91 (s,
White solid, mp 174–175 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.96
(s, 9H), 2.05 (s, 2H), 2.30 (s, 3H), 6.60 (s,1H), 7.08–7.16 (m, 1H), 7.21–
7.26 (m, 2H), 7.27–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3):
19.16,
9H), 1.95 (s, 2H), 2.31 (s, 6H), 6.88 (d, J¼7.60 Hz, 1H), 7.00–7.15 (m,
5H), 7.20–7.30 (m, 1H), 8.11 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
d
21.36, 21.42, 29.66, 31.18, 51.85, 121.44, 124.72, 126.30, 128.47,
29.86, 30.88, 50.20, 127.09, 127.31, 127.84, 128.35, 128.94, 130.12,
132.83, 136.56, 139.49, 139.80, 170.57; HRMS (positive ESI) calcd for
C19H23NO: 304.1677 (MþþNa); found: 304.1660.
128.81, 129.27, 129.64, 130.07, 134.57, 138.04, 138.22, 138.65, 169.93;
HRMS (positive ESI) calcd for C20H25NO: 318.1834 (MþþNa); found:
318.1828.
4.2.22. N-[2-(4-Methyl phenyl)-6-methyl phenyl]-3,3-
4.2.15. N-[2-(3-Bromo phenyl)-5-methyl phenyl]-3,3-
dimethylbutanamide (5l)
dimethylbutanamide (5e)
White solid, mp 151–153 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.98
(s, 9H), 2.06 (s, 2H), 2.29 (s, 3H), 2.38 (s, 3H), 6.59 (s, 1H), 7.09–7.14
(m,1H), 7.15–7.22 (m, 6H); 13C NMR (100 MHz, CDCl3):
19.17, 21.11,
29.71, 30.86, 50.15, 126.99, 127.82, 128.77, 128.99, 129.88, 132.82,
136.43, 136.71, 136.96, 139.23, 170.54; HRMS (positive ESI) calcd for
C20H25NO: 318.1834 (MþþNa); found: 318.1827.
White solid, mp 113–115 ꢀC; 1H NMR (400 MHz, CDCl3):
d 0.93
(s, 9H), 1.98 (s, 2H), 2.31 (s, 3H), 6.85–6.93 (m, 2H), 6.90 (d,
d
J¼7.72 Hz,1H), 7.16–7.28 (m, 2H), 7.40–7.47 (m, 2H), 8.02 (s,1H); 13C
NMR (100 MHz, CDCl3):
d 21.43, 29.71, 31.23, 51.70, 122.30, 122.94,
125.17, 127.99, 128.10, 129.65, 130.40, 130.80, 132.35, 134.37, 138.99,
140.36, 170.07; HRMS (positive ESI) calcd for C19H22BrNO: 382.0782
(MþþNa); found: 382.0772.
4.2.23. N-[2-(3-Methyl phenyl)-6-methyl phenyl]-3,3-
dimethylbutanamide (5m)
4.2.16. N-(2-Phenyl-5-chloro phenyl)-3,3-dimethylbutanamide (5f)
White solid, mp 83–85 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.95 (s,
9H), 2.05 (s, 2H), 2.28 (s, 3H), 2.35 (s, 3H), 6.68 (s, 1H), 7.05–7.16 (m,
4H), 7.18–7.28 (m, 3H), 13C NMR (100 MHz, CDCl3):
19.12, 21.37,
White solid, mp 87–89 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.97 (s,
9H), 2.02 (s, 2H), 7.09–7.15 (m, 3H), 7.28–7.33 (m, 2H), 7.41–7.51 (m,
3H), 8.47 (s, 1H); 13C NMR (100 MHz, CDCl3):
29.60, 31.16, 51.76,
d
d
29.68, 30.80, 50.12, 125.93, 126.93, 127.74, 128.00, 128.19, 129.61,
129.94, 132.79, 136.43, 137.88, 139.42, 139.65, 170.51; HRMS (posi-
tive ESI) calcd for C20H25NO: 318.1834 (MþþNa); found: 318.1837.
120.78, 123.87, 128.30, 129.14, 129.18, 130.02, 130.68, 134.00, 135.83,
137.04, 169.89; HRMS (positive ESI) calcd for C18H20ClNO: 324.1131
(MþþNa); found: 324.1137.
4.2.24. 2-(2,6-Diphenyl phenyl)pyridine (7a)10
4.2.17. N-[2-(4-Methyl phenyl)-5-chloro phenyl]-3,3-
White solid, mp 129–130 ꢀC; 1H NMR (400 MHz, CDCl3):
dimethylbutanamide (5g)
d
6.84–6.91 (m, 2H), 7.05–7.12 (m, 4H), 7.12–7.19 (m, 6H), 7.28 (td,
J¼7.60, 1.72 Hz, 1H), 7.42–7.45 (m, 2H), 7.45–7.55 (m, 1H), 7.28–
7.32 (m, 1H), 13C NMR (100 MHz, CDCl3):
120.95, 126.33, 126.86,
White solid, mp 92–94 ꢀC; 1H NMR (400 MHz, CDCl3):
d 0.96 (s,
9H), 2.01 (s, 2H), 2.40 (s, 3H), 7.05–7.09 (m, 2H), 7.09–7.14 (m,1H), 7.18
d
(d, J¼7.91 Hz, 2H), 7.26 (d, J¼7.91 Hz, 2H), 8.46 (s, 1H); 13C NMR
127.71, 128.26, 129.54, 129.68, 134.96, 138.51, 141.62, 141.88,
148.56, 158.95.
(100 MHz, CDCl3): d 21.98, 29.64, 31.24, 51.78, 120.55, 123.80, 129.00,
129.88,130.76, 133.80, 133.96, 135.88, 138.19, 169.92; HRMS (positive
ESI) calcd for C19H22ClNO: 338.1288 (MþþNa); found: 338.1240.
4.2.25. 2-[2,6-Di(4-methylphenyl)phenyl]pyridine (7b)11
White solid, mp 146–148 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.16
4.2.18. N-[2-(3-Methoxyl phenyl)-5-chloro phenyl]-3,3-
(s, 6H), 6.80–6.91 (m, 10H), 7.20 (td, J¼7.72, 1.62 Hz, 1H), 7.29–7.34
dimethylbutanamide (5h)
(m, 2H), 7.36–7.42 (m, 1H), 8.24 (d, J¼4.80 Hz, 1H); 13C NMR
White solid, mp 67–70 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.98 (s,
(100 MHz, CDCl3): d 21.08, 120.84, 126.83, 128.17, 128.39, 129.37,
9H), 2.04 (s, 2H), 3.83 (s, 3H), 6.82–6.85 (m, 1H), 6.86–6.91 (m, 1H),
129.51, 135.00, 135.81, 138.33, 138.69, 141.77, 148.42, 159.18.
6.95–6.98 (m, 1H), 7.08–7.19 (m, 3H), 7.40 (t, J¼7.94 Hz, 1H), 8.49 (s,
1H); 13C NMR (100 MHz, CDCl3):
d
29.64, 31.23, 51.85, 55.31, 113.81,
4.2.26. 2-[2,6-Di(3-methoxylphenyl)phenyl]pyridine (7c)
114.79, 120.55, 121.23, 123.78, 129.74, 130.26, 130.57, 134.08, 135.84,
138.37, 160.15, 169.96; HRMS (positive ESI) calcd for C19H22ClNO2:
354.1237 (MþþNa); found: 354.1242.
White solid, mp 172–174 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.20
(s, 6H), 6.80–7.04 (m, 10H), 7.29 (td, J¼7.72, 1.47 Hz, 1H), 7.39–7.44
(m, 2H), 7.46–7.52 (m, 1H), 8.30–8.32 (m, 1H); 13C NMR (100 MHz,

F. Yang et al. / Tetrahedron 65 (2009) 914–919
919
CDCl3):
d
21.36, 120.84, 126.73,126.85, 127.03,127.49,128.17, 129.39,
References and notes
130.60, 134.90, 137.24, 138.48, 141.54, 141.92, 148.40, 159.16; HRMS
(positive ESI) calcd for C25H21NO2: 368.1651 (MþþH); found:
368.1648.
1. (a) Bergman, R. G. Nature 2007, 446, 391; (b) Ellman, J. A. Science 2007, 316,
1131; (c) Godula, K.; Sames, D. Science 2006, 312, 67; (d) Stuart, D. R.; Fagnou, K.
Science 2007, 316, 1172.
2. For recent representative reviews, see: (a) Herrerıas, C. I.; Yao, X.-Q.; Li, Z.-P.; Li,
C.-J. Chem. Rev. 2007, 107, 2546; (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
Rev. 2007, 107, 174.
4.2.27. 2-[2,6-Di(3-methylphenyl)phenyl]pyridine (7d)
White solid, mp 76–78 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.20
3. For selected examples on C–H bonds functionalization with a directing-group,
see: (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc.
2005, 127, 7330; (b) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 9879; (c) Yang, S.-D.; Li, B.-J.; Wan, X.-B.; Shi, Z.-J. J. Am. Chem. Soc.
2007, 129, 6066; (d) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2112; (e) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783; (f) Den-
mark, S. E.; Kallemeyn, J. M. J. Am. Chem. Soc. 2006, 128, 15958; (g) Thu, H.-Y.;
Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048; (h) Matsuura, Y.; Tamura,
M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858;
(i) Zhang, Y.-H.; Feng, J.-Q.; Li, C.-J. J. Am. Chem. Soc. 2008, 130, 2900; (j) Xia,
J.-B.; You, S.-L. Organometallics 2007, 26, 4869.
4. For selected examples on C–H bonds functionalization of free arenes, see: (a)
Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; (b) Deprez,
N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972; (c)
Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
581; (d) Terao, Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura, M. J.
Org. Chem. 2003, 68, 5236; (e) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc.
2004, 126, 5074; (f) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2007, 129, 5332; (g) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449; (h)
Murphy, J. M.; Liao, X.-B.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434.
5. (a) Zhao, J.; Campo, M.; Larock, R. C. Angew. Chem., Int. Ed. 2005, 44, 1873; (b)
Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485; (c) Thalji, R. K.; Ellman,
J. A.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192.
(s, 6H), 6.80–7.04 (m, 10H), 7.29 (td, J¼7.62, 1.65 Hz, 1H), 7.39–
7.44 (m, 2H), 7.46–7.52 (m, 1H), 8.29–8.33 (m, 1H); 13C NMR
(100 MHz, CDCl3):
d 21.19, 120.70, 126.59, 126.71, 126.89, 127.34,
128.01, 129.22, 130.46, 134.75, 137.06, 138.33, 141.40, 141.80,
148.21, 159.03; HRMS (positive ESI) calcd for C25H21N: 336.1752
(MþþH); found: 336.1747.
4.2.28. 2-[2,6-Di(3-bromophenyl)phenyl]pyridine (7e)
White solid, mp 122–123 ꢀC; 1H NMR (400 MHz, CDCl3):
d 6.83–
6.90 (m, 1H), 6.93–7.04 (m, 5H), 7.24–7.32 (m, 4H), 7.37 (td, J¼7.68,
1.70 Hz, 1H), 7.40–7.45 (m, 2H), 7.48–7.55 (m, 1H), 8.33–8.38 (m,
1H); 13C NMR (100 MHz, CDCl3):
d 121.46, 121.86, 126.72, 128.28,
128.52, 129.20, 129.55, 129.79, 132.59, 135.39, 138.47, 140.47, 143.36,
148.78, 158.02; HRMS (positive ESI) calcd for C23H15Br2N: 463.9649
(MþþH); found: 463.9642.
6. Yang, F.; Wu, Y.-J.; Zhu, Z.-W.; Zhang, J.-L.; Li, Y.-N. Tetrahedron 2008, 64,
6782.
Acknowledgements
7. Yoshifuji, M.; Nagase, R.; Inamoto, N. Bull. Chem. Soc. Jpn. 1982, 55, 873.
8. Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211.
9. Ranu, B. C.; Dey, S. S.; Hajra, A. Green Chem. 2003, 5, 44.
10. Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439.
11. Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 3,
2579.
We are grateful to the National Natural Science Foundation of
China (No. 20772114) and the Innovation Fund for Outstanding
Scholar of Henan Province (No. 0621001100) for financial support of
this research.