Direct ortho-arylation of 2-arylbenzoxazoles via C-H activation

Article abstract of DOI:10.1016/j.tet.2008.04.099

A new and highly regioselective arylation of 2-arylbenzoxazoles based on C-H activation has been developed. The results represent the first examples of palladium-catalyzed direct ortho-arylation of 2-arylbenzoxazoles and also provide a facile route for the synthesis of complicated structures containing arylated benzoxazoles moieties.

Full text of DOI:10.1016/j.tet.2008.04.099

Tetrahedron 64 (2008) 6782–6787
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct ortho-arylation of 2-arylbenzoxazoles via C–H activation
*
Fan Yang, Yangjie Wu , Zhiwu Zhu, Junli Zhang, Yanan Li
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
Article history:
A new and highly regioselective arylation of 2-arylbenzoxazoles based on C–H activation has been
developed. The results represent the first examples of palladium-catalyzed direct ortho-arylation of
2-arylbenzoxazoles and also provide a facile route for the synthesis of complicated structures containing
arylated benzoxazoles moieties.
Received 21 February 2008
Received in revised form 22 April 2008
Accepted 25 April 2008
Available online 30 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Arylation
C–C coupling
Palladium catalysis
C–H activation
1. Introduction
diphenyliodonium salts under Pd(II) catalysis has been studied by
Sanford et al.4a However, the scope of the reactions involving the
Palladium-catalyzed C–C cross-coupling of aryl halides with
a nucleophilic compound is increasingly becoming a preferred
method in synthetic applications.1 The method typically requires
a highly reactive organometallic reagent (e.g., RSnR03, Stille;
RB(OH)2, Suzuki–Miyaura; RMgX, Kumada; and RZnX, Negishi) as
the nucleophilic compound.2 However, preparation of preactivated
reagents often is a multi-step therefore time-consuming and
economically inefficient process. An attractive alternative to this
approach is to treat the aryl C–H bond as a functional group, sub-
sequently achieving direct and selective replacement of C–H bonds
with new bonds (such as C–C, C–O, and C–N) thereby yielding the
desired products. This alternative would represent an ideal and
environmentally friendly method for the construction of compli-
cated structures.3
During the last few years, transition-metal-catalyzed direct
arylation of the aryl C–H bond has emerged as a fascinating area
rich in challenges and opportunities, and lately been realized in
many arenes with or without a directing group.4,5 With a directing
group such as pyridine, imine, acetamine, carboxylic acid, or
oxazoline, ortho-C–H bond can be highly regioselectively
functionalized under palladium, ruthenium, or rhodium catalysis
(Scheme 1).4 In particular, palladium-promoted functionalization
of C–H bond has shown its unique advantages. Notably, the aryl-
ation of 2-arylpyridines and other nitrogen heterocycles with
various directing groups is still relatively limited and should be
extended and investigated further.
DG
DG
DG
FG
FG
FG
Functionalization
+
R
R
R
DG = Directing Group, FG = Functional Group
Scheme 1. Functionalization of ortho-C–H bond via C–H activation.
Arylated benzoxazoles are the important biaryl pharmacophore
and with lower toxicities, which have exhibited a variety of bi-
ological activities, including anti-HIV, antiinflammatory, antimi-
crobial, antibiotic, and antitumor properties.6 Further extension
and branching functional substituents on them would have valu-
able significance for the synthesis of pharmaceutical intermediates.
In this work, we report for the first time successful direct arylation
of 2-arylbenzoxazoles through ortho-C–H activation by coupling
with aryl iodides.
2. Results and discussion
Reaction conditions were screened with respect to the additive
and solvent using 2-phenylbenzoxazole (1a) and iodobenzene (2a)
as the substrates (Table 1). After various additives such as
Cu(OAc)2$H2O, BQ, K2S2O8, and AgOAc were examined, AgOAc gave
the best result with a yield of 66% (entries 1–7). When the loading
* Corresponding author. Tel./fax: þ86 371 67766667.
E-mail address: wyj@zzu.edu.cn (Y. Wu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.099

F. Yang et al. / Tetrahedron 64 (2008) 6782–6787
6783
Table 1
Table 2 (continued)
ortho-Arylation of 2-phenylbenzoxazole via C–H activation under different
Entry
R
2
Product
Time Yieldb
(h) (%)
conditionsa
DG
DG
DG
Ph
Ph
Ph
DG
Pd(OAc)2, Additive
Solvent
O
N
+
+
PhI
3-Cl
(1c)
5
2a
83
76 (3ca)
85 (3cb)
DG=
1a
2a
3aa
4aa
Cl
Entry Additive (equiv)
Solvent
Yieldb (%) Ratio (3aa/4aa)
DG
1
2
3
4
5
6
7
8
Cu(OAc)2$H2O (2.4)
BQ (2.4)
K2S2O8 (2.4)
Cu(OAc)2$H2O/BQ (1.2/1.2)
AgOAc/BQ (1.2/1.2)
AgOAc/Cu(OAc)2$H2O (1.2/1.2) TFA
AgOAc (2.4)
AgOAc (4.8)
AgOAc (4.8)
AgOAc (4.8)
AgOAc (4.8)
TFA
TFA
TFA
TFA
TFA
<5
<5
6
11
16
13
66
88
18
100:0
100:0
100:0
14:86
75:25
70:30
55:45
35:65
100:0
100:0
20:80
6
1c
1c
2b
72
Cl
DG
DG
TFA
TFA
7
8
2c
2a
161
43
50 (3cc)
93 (3da)
Br
9
10
11
HOAc
1,4-Dioxane <5
DMA <5
Cl
a
All the reactions were carried out in the presence of 0.25 mmol 1a, 1.0 mmol 2a,
3-Me
(1d)
and 5 mol % Pd(OAc)2 in 0.6 mL solvent under reflux for 72 h.
b
Yields are given for isolated products of 3aa and 4aa.
of AgOAc was increased to 4.8 equiv, the reaction rate was
enhanced and 88% total yield of monophenylated product 3aa and
diphenylated product 4aa was obtained with a 3aa/4aa ratio of
35:65 (entry 8). However, when the solvent was changed to HOAc,
the reaction proceeded very slowly (entry 9). Aprotic polar solvents,
for example, 1,4-dioxane and DMA, examined in combination with
Pd(OAc)2 and AgOAc, did not exhibit comparably favorable results
(entries 10 and 11).
Under above optimized conditions, the scope of the substrates
was also surveyed (Table 2). The reaction was compatible with
bromo substituent on the aryl iodides (entries 4, 7, 10, and 16) and
bromo or chloro substituents on 2-arylbenzoxazoles (entries 2–7).
These characteristics would permit construction of scaffolds that
DG
DG
9
1d
1d
1d
2b
2c
40
96
58
90 (3db)
82 (3dc)
75 (3dd)
10
11
Br
DG
3-MeO-
C6H4I (2d)
OMe
COMe
Table 2
DG
ortho-Arylation of 2-arylbenzoxazoles via C–H activationa
4-MeCO-
C6H4I (2e)
12
13
14
1d
1d
142
d
34 (3de)
d
DG
DG
DG
Ar
Ar
Ar
Pd(OAc)2, AgOAc
TFA
+
ArI
or
2-Cl-C6H5I
(2f)
d
R
R
R
1
2
3
4
DG
Entry
1c
R
2
Product
Time Yieldb
3,4-
MeO (1e)
2a
86
80 (3ea)
(h)
(%)
MeO
OMe
DG
H
4-Me-
72
70 (4ab)
(1a)
C6H4I (2b)
DG
15
16
1e
1e
2b
2c
74
84 (3eb)
DG
MeO
3-Br
(1b)
C6H5I
(2a)
2
72
92 (3ba)
95 (3bb)
OMe
DG
Br
DG
DG
Br
170
60 (3ec)
3
4
1b
1b
2b
100
175
MeO
OMe
Br
17
2,4-Cl (1f) 2a
d
d
d
3-Br-
C6H4I (2c)
a
80 (3bc)
All the reactions were carried out in the presence of 0.25 mmol 1, 1.0 mmol 2,
Br
1.2 mmol AgOAc, and 5 mol % Pd(OAc)2 in 0.6 mL TFA under reflux.
b
Br
Yields are given for isolated products.
Approximately 12% of 3ab was also obtained.
c
(continued)

6784
F. Yang et al. / Tetrahedron 64 (2008) 6782–6787
catalytic cycle.9 Step (ii) is proposed to be an oxidative addition of
Pd(II) to unstable Pd(IV) species. And the final step (iii) is a re-
ductive elimination process, which results in the desired product.10
3. Conclusion
In summary, we have developed a highly regioselective method
for arylation of 2-arylbenzoxazoles based on C–H activation. The
reaction could tolerate various functional groups, and allows bromo
or chloro substituents on 2-arylbenzoxazoles and bromo sub-
stituent on aryl iodides. The arylation exhibits high regioselectivity
for 2-arylbenzoxazoles containing a meta-substituent and the
arylated product of the less sterically hindered ortho-C–H bond was
observed as the major product. Current studies are focused on
further exploration of the substrate scope and synthetic utility of
this methodology.
4. Experimental
4.1. General methods
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 and AgOAc were synthesized according to the liter-
atures.6c,11 DMA and 1,4-dioxane were purified by the standard
methods. CH2Cl2 (analytical grade) was stored over molecular
sieves and used without further purification. Ethyl acetate and
hexane (reagent grade) were used for column chromatography
without purification. The other chemicals were bought from com-
mercial sources and used as-received unless otherwise noted.
Figure 1. Molecular structure of 3ba.
could be functionalized through conventional Pd(0)/Pd(II) coupling
processes. Electronic factors had a critical effect on the reactivity of
the substrate and electron-donating substituents on either 2-aryl-
benzoxazoles or aryl iodides would speed up the arylation, and vice
versa. The reaction of iodides containing electron-neutral, electron-
donating (CH3), or moderately electron-withdrawing (Br) sub-
stituents proceeded well and moderate-to-good yields were
obtained. However, in the case of iodides containing strongly
electron-withdrawing groups (CH3CO), the reactions were much
slower and gave a yield of 34% (entry 12). And the arylated product
of 2-arylbenzoxazole with aryl iodide containing a chloro group
was not detected (entry 13). Similarly, the arylation of 2-arylben-
zoxazoles containing two moderately electron-withdrawing (Cl)
substituents with iodobenzene (2a) could not proceed and no
product was observed (entry 17). Generally, for 2-arylbenzoxazoles
containing a meta-substituent, high regioselectivity was observed
for arylation of the less sterically hindered ortho-C–H bond. In case
there is more than one possible substitution, the diarylation
product could be obtained as the major product after a prolonged
time (entry 1). The molecular structure of 3ba was unambiguously
determined by the single crystal X-ray diffraction study (Fig. 1).7
A possible reaction mechanism for the arylation of 2-arylbenz-
oxazole is outlined in Scheme 2. As an electrophilic C–H activation
process, the reactions are faster when either 2-arylbenzoxazoles or
aryl iodides possess the electron-donating substituents. Step (i) is
cyclopalladation of 2-arylbenzoxazoles via C–H activation to afford
a cyclopalladated intermediate. The ortho-alkylation of 2-arylox-
azolines through the reaction of their cyclopalladated complexes
with alkyl iodides provides the strong support for this proposed
step.8 We have found that reactions of aryl iodides containing
electron-donating groups proceeded much faster than those of aryl
iodides containing electron-withdrawing groups. The finding sets
the current process apart from the conventional Pd(0)/Pd(II)
4.2. General procedure for synthesis of 2-arylbenzoxazoles
To a solution of 2-aminophenol (0.109 g, 1.0 mmol) in MeOH
(15 mL), aldehyde (1.0 mmol) was added. The resulting mixture
was heated at 45 ꢀC for 12 h. After concentration under reduced
pressure, the residue was dissolved in CH2Cl2 (25 mL) and Ag2O
(1.1 mmol) was then added. After stirring at room temperature for
5 h, the insoluble material was filtered off. The filtrate was evapo-
rated and the residue was purified by flash column chromatogra-
phy (hexane/ethyl acetate) to afford the desired product.
4.2.1. 2-Phenylbenzoxazole (1a)11a
White solid, mp 79–80 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.30–7.40 (m, 2H), 7.40–7.60 (m, 4H), 7.72–7.80 (m, 1H), 8.26 (t,
J¼2.40 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 110.60,120.03,124.58,
125.11, 127.18, 127.63, 128.92, 131.53, 142.11, 150.77, 163.05; MS, m/z
(%): 196.1 (100) [MþþH].
4.2.2. 2-(3-Bromo phenyl) benzoxazole (1b)12
White solid, mp 128–130 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.25–7.44 (m, 3H), 7.56–7.65 (m, 1H), 7.65–7.69 (m, 1H), 7.76–7.81
(m, 1H), 8.20 (d, J¼8.02 Hz, 1H), 8.43 (s, 1H); 13C NMR (100 MHz,
C
H
L
L
C
CDCl3):
d 110.74, 120.22, 123.04, 124.87, 125.60, 126.12, 129.02,
PdII
ArI
Pd
C
i) Cyclometallation
iii) Reductive elimination
130.49, 130.54, 134.46, 141.80, 150.78, 161.50; MS, m/z (%): 274.4
(100) [MþþH].
I
ii) Oxidative addition
Ar
L
L
C
4.2.3. 2-(3-Chloro phenyl) benzoxazole (1c)12
PdIV
Ar
+ AgI
White solid, mp 124–125 ꢀC; 1H NMR (400 MHz, CDCl3):
AgOAc
L = Directing Group
d
7.35–7.40 (m, 2H), 7.44–7.53 (m, 2H), 7.58–7.62 (m, 1H), 7.77–7.79
Scheme 2. Proposed catalytic cycle.
(m, 1H), 8.15 (dt, J¼7.60, 1.40 Hz, 1H), 8.27 (d, J¼1.60 Hz, 1H); 13C

F. Yang et al. / Tetrahedron 64 (2008) 6782–6787
6785
NMR (100 MHz, CDCl3):
d
110.74, 120.19, 124.87, 125.60, 125.67,
4.3.4. 2-[2,6-Di(4-methyl phenyl) phenyl] benzoxazole (4ab)
127.63, 128.75, 130.27, 131.56, 135.08, 141.74, 150.74, 161.64; MS, m/z
(%): 230.4 (100) [MþþH].
White solid, mp 146–148 ꢀC; 1H NMR (400 MHz, CDCl3):
d
2.21
(s, 6H), 6.96 (d, J¼8.00 Hz, 4H), 7.11 (d, J¼8.00 Hz, 4H), 7.15–7.23 (m,
2H), 7.23–7.31 (m, 1H), 7.45 (d, J¼7.72 Hz, 2H), 7.51–7.61 (m, 2H);
4.2.4. 2-(3-Methyl phenyl) benzoxazole (1d)13
13C NMR (100 MHz, CDCl3):
d 20.97, 110.35, 120.11, 123.79, 124.55,
White solid, mp 79–80 ꢀC; 1H NMR (400 MHz, CDCl3):
d
2.45 (s,
126.13, 128.30, 128.83, 128.97, 130.35, 136.75, 137.53, 141.19, 143.66,
150.13, 162.34; HRMS (positive ESI) calcd for C27H21NO (MHþ):
376.1701, found: 376.1699.
3H), 7.24–7.79 (m, 3H), 7.37–7.42 (m, 1H), 7.56–7.60 (m, 1H),
7.75–7.80 (m, 1H), 8.05 (d, J¼7.80 Hz, 1H), 8.08 (s, 1H); 13C NMR
(100 MHz, CDCl3):
d 21.36, 110.57, 119.92, 124.57, 124.76, 125.06,
126.92, 128.20, 128.83, 132.42, 138.76, 141.97, 150.69, 163.24; MS,
4.3.5. 2-(2-Phenyl-5-bromo phenyl) benzoxazole (3ba)
m/z (%): 232.2 (100) [MþþH].
White solid, mp 113–115 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.22–7.29 (m, 4H), 7.29–7.38 (m, 5H) 7.67–7.74 (m, 2H), 8.29 (d,
4.2.5. 2-(3,4-Dimethoxyl phenyl) benzoxazole (1e)12
J¼2.04 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 110.59, 120.23, 121.45,
White solid, mp 109–111 ꢀC; 1H NMR (400 MHz, CDCl3):
d
3.97
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; HRMS (positive ESI) calcd for
(s, 3H), 4.02 (s, 3H), 6.98 (d, J¼0.88 Hz, 1H), 7.25–7.36 (m, 2H),
7.54–7.58 (m, 1H), 7.73–7.78 (m, 2H), 7.86 (d, J¼8.40 Hz, 1H); 13C
C
19H12BrNO (MHþ): 350.0181, found: 350.0196.
NMR (100 MHz, CDCl3): d 56.05, 56.14,109.99, 110.41, 110.98, 119.58,
119.67, 121.21, 124.52, 124.74, 142.07, 149.21, 150.65, 151.99, 163.13;
4.3.6. 2-[2-(4-Methyl phenyl)-5-bromo phenyl] benzoxazole (3bb)
White solid, mp 142–144 ꢀC; 1H NMR (400 MHz, CDCl3):
2.36
MS, m/z (%): 256.3 (100) [MþþH].
d
(s, 3H), 7.08–7.15 (m, 4H), 7.26–7.35 (m, 4H), 7.67 (dd, J¼8.00,
4.2.6. 2-(2,4-Dichloro phenyl) benzoxazole (1f)14
2.04 Hz, 1H), 7.70–7.75 (m, 1H), 8.25 (d, J¼2.08 Hz, 1H); 13C NMR
White solid, mp 123–124 ꢀC; 1H NMR (400 MHz, CDCl3):
(100 MHz, CDCl3): d 21.20, 110.65, 120.23, 121.16, 124.49, 125.24,
d
7.38–7.44 (m, 3H), 7.58–7.65 (m, 2H), 7.83–7.87 (m, 1H), 8.13 (d,
127.82, 128.51, 128.97, 132.71, 133.61, 133.88, 136.81, 137.40, 141.27,
141.45, 150.70, 162.44; HRMS (positive ESI) calcd for C20H14BrNO
(MHþ): 364.0337, found: 364.0334.
J¼8.40 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 110.77, 120.56, 124.72,
124.82, 125.80, 127.44, 131.30, 132.52, 134.23, 137.54, 141.58, 150.50,
160.07; MS, m/z (%): 264.5 (100) [MþþH].
4.3.7. 2-[2-(3-Bromo phenyl)-5-bromo phenyl] benzoxazole (3bc)
4.3. General procedure for arylation of 2-arylbenzoxazoles
White solid, mp 102–105 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.05–7.13 (m, 1H), 7.13–7.18 (m, 1H), 7.26–7.34 (m, 4H), 7.45–7.51
2-Arylbenzoxazole (0.25 mmol), aryl iodide (1.0 mmol), palla-
dium acetate (5 mol %), and silver acetate (1.2 mmol) were
dissolved in trifluoroacetic acid (0.6 mL) in a 5 mL vial under at-
mospheric air and heated under reflux. The reaction process was
monitored by GC analysis. During this time, a yellow precipitate
was formed. After the reaction was complete, the mixture was di-
luted with CH2Cl2 (10 mL), filtered through a pad of Celite, and
washed multiple times with CH2Cl2. The combined organic solu-
tions were evaporated under reduced pressure and the residue was
purified by flash chromatography on silica gel (ethyl acetate/hex-
ane) to give the pure product.
(m, 2H), 7.60–7.73 (m, 2H), 8.32 (d, J¼2.08 Hz, 1H); 13C NMR
(100 MHz, CDCl3):
d 110.61, 120.31, 122.09, 122.18, 124.65, 125.49,
127.54, 127.74, 129.55, 130.64, 131.63, 132.61, 133.51, 133.93, 139.53,
141.37, 141.91, 150.62, 161.60; HRMS (positive ESI) calcd for
C
19H11Br2NO (MHþ): 429.9265, found: 429.9261.
4.3.8. 2-(2-Phenyl-5-chloro phenyl) benzoxazole (3ca)
White solid, mp 88–90 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.22–7.28 (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 (100 MHz, CDCl3):
110.59, 120.23, 124.52, 125.28, 127.57,
d
127.61, 128.19, 128.72, 130.66, 130.94, 132.49, 133.62, 139.83, 140.82,
141.43, 150.68, 162.39; HRMS (positive ESI) calcd for C19H12ClNO
(MHþ): 306.0685, found: 306.0661.
4.3.1. 2-(2-Phenyl phenyl) benzoxazole (3aa)
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,
4.3.9. 2-[2-(4-Methyl phenyl)-5-chloro phenyl] benzoxazole (3cb)
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; HRMS (positive ESI)
calcd for C19H13NO (MHþ): 272.1075, found: 272.1075.
White solid, mp 112–115 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.37
(s, 3H), 7.11–7.15 (m, 4H), 7.27–7.35 (m, 3H), 7.38–7.43 (m, 1H), 7.53
(dd, J¼8.00, 2.24 Hz, 1H), 7.72 (m, 1H), 8.10 (d, J¼2.24 Hz, 1H); 13C
NMR (100 MHz, CDCl3):
d 21.21, 110.67, 120.26, 124.49, 125.24,
4.3.2. 2-(2,6-Diphenyl phenyl) benzoxazole (4aa)
127.59, 128.59, 128.97, 130.75, 130.94, 132.52, 133.35, 136.82, 137.38,
140.83, 141.51, 150.72, 162.59; HRMS (positive ESI) calcd for
White solid, mp 138–140 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.10–7.25 (m, 13H), 7.35–7.75 (m, 3H), 7.61 (t, J¼7.60 Hz, 1H); 13C
C
20H14ClNO (MHþ): 320.0842, found: 320.0853.
NMR (100 MHz, CDCl3):
d 110.35, 120.16, 123.98, 124.75, 126.35,
127.21, 128.17, 128.53, 129.22, 130.50, 140.49, 141.13, 143.80, 150.16,
162.16; HRMS (positive ESI) calcd for C25H17NO (MHþ): 348.1388,
found: 348.1392.
4.3.10. 2-[2-(3-Bromo phenyl)-5-chloro phenyl] benzoxazole (3cc)
White solid, mp 113–114 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.10–7.20 (m, 2H), 7.28–7.36 (m, 3H), 7.38 (d, J¼8.00 Hz, 1H), 7.46–
7.52 (m, 2H), 7.54 (dd, J¼8.00, 2.24 Hz, 1H), 7.68–7.73 (m, 1H), 8.19
4.3.3. 2-[2-(4-Methyl phenyl) phenyl] benzoxazole (3ab)
(d, J¼2.24 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 110.62, 120.31,
Light yellow solid, mp 88–90 ꢀC; 1H NMR (400 MHz, CDCl3):
122.17, 124.66, 125.49, 127.51, 127.61, 129.54, 130.64, 131.00, 131.71,
132.44,134.24, 139.10, 141.37, 141.90, 150.63, 161.75; HRMS (positive
ESI) calcd for C19H11BrClNO (MHþ): 383.9791, found: 383.9799.
d
2.36 (s, 3H), 7.12 (d, J¼8.00 Hz, 2H), 7.17 (d, J¼8.00 Hz, 2H),
7.24–7.34 (m, 3H), 7.40–7.52 (m, 2H), 7.52–7.60 (m, 1H), 7.70–7.75
(m, 1H), 8.03–8.11 (m, 1H); 13C NMR (100 MHz, CDCl3):
21.17,
d
110.57, 120.06, 124.25, 124.84, 126.24, 127.27, 128.63, 128.86, 130.96,
131.04, 131.14, 136.96, 137.93, 141.71, 142.40, 150.74, 164.02; HRMS
(positive ESI) calcd for
286.1230.
4.3.11. 2-(2-Phenyl-5-methyl phenyl) benzoxazole (3da)
Light yellow oil; 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, 123.29,
C
20H15NO (MHþ): 286.1232, found:
d

6786
F. Yang et al. / Tetrahedron 64 (2008) 6782–6787
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; HRMS (positive ESI) calcd for
C
3H), 7.45–7.50 (m, 1H), 7.52–7.56 (m, 1H), 7.66–7.72 (m, 2H); 13C
NMR (100 MHz, CDCl3): 56.15, 56.27, 110.39, 112.92, 113.68, 118.11,
119.73, 121.99, 124.37, 124.79, 127.92, 129.37, 130.15, 131.85, 134.43,
141.49, 143.17, 148.59, 150.54, 150.98, 163.29; HRMS (positive ESI)
calcd for C21H16BrNO3 (MHþ): 410.0392, found: 410.0388.
d
20H15NO (MHþ): 286.1232, found: 286.1235.
4.3.12. 2-[2-(4-Methyl phenyl)-5-methyl phenyl] benzoxazole
(3db)
White solid, mp 111–114 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.34
4.4. Crystal structure determination
(s, 3H), 2.45 (s, 3H), 7.07–7.12 (m, 2H), 7.12–7.18 (m, 2H), 7.20–7.31
(m, 3H), 7.31–7.37 (m, 2H), 7.68–7.74 (m, 1H), 7.91 (s, 1H); 13C NMR
Intensity data of 3ba were measured on a Rigaku-Raxis-IV X-ray
(100 MHz, CDCl3):
d 20.95, 21.22, 110.61, 120.04, 124.29, 124.84,
diffractometer using graphite monochromated Mo K
a radiation
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; HRMS (positive ESI) calcd for
(
l
¼0.71073 Å). The data were corrected for Lorentz and polariza-
tion factors. The structure was solved by direct methods,15 ex-
panded using Fourier techniques, and refined by full-matrix
least-squares methods. All calculations were performed using the
TEXSAN crystallographic software package of Molecular Structure
Corporation.
C
21H17NO (MHþ): 300.1388, found: 300.1389.
4.3.13. 2-[2-(3-Bromo phenyl)-5-methyl phenyl] benzoxazole (3dc)
Light yellow oil; 1H NMR (400 MHz, CDCl3):
2.46 (s, 3H),
d
7.08–7.15 (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
5. Supplementary material
(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; HRMS (positive ESI) calcd for
C
CCDC 684234 contains the supplementary crystallographic data
for 3ba, which can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
20H14BrNO (MHþ): 364.0337, found: 364.0327.
4.3.14. 2-[2-(3-Methoxyl phenyl)-5-methyl phenyl] benzoxazole
(3dd)
White solid, mp 111–113 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.46
Acknowledgements
(s, 3H), 3.66 (s, 3H), 6.80–6.91 (m, 3H), 7.14–7.23 (m, 1H), 7.23–7.32
(m, 3H), 7.35–7.40 (m, 2H), 7.16 (dd, J¼7.60, 1.84 Hz, 1H), 7.91 (s,
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
to this research.
1H); 13C NMR (100 MHz, CDCl3):
d 20.97, 55.17, 110.58, 113.05,
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; HRMS
(positive ESI) calcd for
316.1340.
C
21H17NO2 (MHþ): 316.1338, found:
References and notes
4.3.15. 2-[2-(4-Acetyl phenyl)-5-methyl phenyl] benzoxazole (3de)
White solid, mp 169–172 ꢀC; 1H NMR (400 MHz, CDCl3):
2.50
(s, 3H), 2.61 (s, 3H), 7.26–7.32 (m, 3H), 7.32–7.39 (m, 3H), 7.39–7.44
1. (a) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651–2710; (b) Hassan, J.;
Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359–1469.
d
2. (a) Metal-Catalyzed Cross-Coupling Reactions; Dieterich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, NY, 1998; (b) Knight, D. W. Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
pp 481–520.
(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; HRMS (positive ESI)
calcd for C22H17NO2 (MHþ): 328.1338, found: 328.1341.
3. For recent representative reviews, see: (a) Bergman, R. G. Nature 2007,
446, 391–393; (b) Ellman, J. A. Science 2007, 316, 1131–1132; (c) Godula,
K.; Sames, D. Science 2006, 312, 67–72; (d) Yu, J.-Q.; Giri, R.; Chen, X.
Org. Biomol. Chem. 2006, 4, 4041–4047; (e) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439–2463; (f) Daugulis, O.; Zaitsev, V. G.; Shaba-
shov, D.; Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382–3388; (g) Herrerıas,
C. I.; Yao, X.-Q.; Li, Z.-P.; Li, C.-J. Chem. Rev. 2007, 107, 2546–2562; (h)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238; (i)
Catellani, M.; Motti, E.; Faccini, F.; Ferraccioli, R. Pure Appl. Chem. 2005,
77, 1243–1248.
4. For recent representative examples on transition-metal-catalyzed direct
arylation with a directing group, see: (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331; (b) Yang, S.-D.; Li, B.-J.;
Wan, X.-B.; Shi, Z.-J. J. Am. Chem. Soc. 2007, 129, 6066–6067; (c) Shabashov, D.;
Daugulis, O. Org. Lett. 2006, 8, 4947–4949; (d) Giri, R.; Chen, X.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2005, 44, 2112–2115; (e) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org.
Lett. 2002, 4, 1783–1785; (f) Denmark, S. E.; Kallemeyn, J. M. J. Am. Chem. Soc.
2006, 128, 15958–15959; (g) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc.
2006, 128, 9048–9049.
5. For recent representative examples on transition-metal-catalyzed C–H
activation without a directing group, see: (a) Lane, B. S.; Brown, M. A.; Sames, D.
J. Am. Chem. Soc. 2005, 127, 8050–8057; (b) Deprez, N. R.; Kalyani, D.; Krause, A.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972–4973; (c) Campeau, L.-C.;
Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581–590; (d) Terao,
Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem. 2003,
68, 5236–5243.
6. (a) Sondhi, S. M.; Singh, N.; Kumar, A.; Lozach, O.; Meijer, L. Bioorg. Med. Chem.
2006, 14, 3758–3765; (b) Rida, S. M.; Ashour, F. A.; El-Hawash, S. A. M.;
ElSemary, M. M.; Badr, M. H.; Shalaby, M. A. Eur. J. Med. Chem. 2005, 40,
949–959; (c) Chang, J.-B.; Zhao, K.; Pan, S.-F. Tetrahedron Lett. 2002, 43,
951–954.
4.3.16. 2-[2-Phenyl-4,5-dimethoxyl phenyl] benzoxazole (3ea)
White solid, mp 129–132 ꢀC; 1H NMR (400 MHz, CDCl3):
d 3.97
(s, 3H), 4.02 (s, 3H), 6.93 (s, 1H), 7.20–7.24 (m, 2H), 7.27–7.31 (m,
3H), 7.32–7.36 (m, 3H), 7.67 (s, 1H), 7.68–7.72 (m, 1H); 13C NMR
(100 MHz, CDCl3):
d 56.09, 56.25, 110.39, 113.01, 113.83, 118.13,
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; HRMS (positive ESI) calcd for
C
21H17NO3 (MHþ): 332.1286, found: 332.1276.
4.3.17. 2-[2-(4-Methyl phenyl)-4,5-dimethoxyl phenyl] benzoxazole
(3eb)
White solid, mp 142–145 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.29
(s, 3H), 3.87 (s, 3H), 3.93 (s, 3H), 6.83 (s, 1H), 7.03–7.14 (m, 4H),
7.14–7.22 (m, 3H), 7.55 (s, 1H), 7.59–7.63 (m, 1H); 13C NMR
(100 MHz, CDCl3): d 21.17, 56.04, 56.22, 110.43,113.12, 113.89,118.10,
119.68, 124.20, 124.55, 128.77, 136.18, 136.80, 138.10, 141.67, 148.10,
150.62, 150.91, 164.03; HRMS (positive ESI) calcd for C22H19NO3
(MHþ): 346.1443, found: 346.1440.
4.3.18. 2-[2-(3-Bromo phenyl)-4,5-dimethoxyl phenyl] benzoxazole
(3ec)
7. Crystal data for 3ba:
C
19H12BrNO, MW¼350.21, triclinic, space group Pꢁ1,
White solid, mp 167–170 ꢀC; 1H NMR (400 MHz, CDCl3):
d
3.97
T¼291(2) K, a¼5.9079(12) Å, b¼8.6366(17) Å, c¼14.747(3) Å,
a
¼90.28(3)ꢀ,
(s, 3H), 4.03 (s, 3H), 6.87 (s, 1H), 7.14–7.19 (m, 2H), 7.23–7.30 (m,
b
¼100.58(3)ꢀ,
g
¼93.44(3)ꢀ, V¼738.3(3) Å3, Z¼2, reflections collected/unique:

F. Yang et al. / Tetrahedron 64 (2008) 6782–6787
6787
2222/2222 (Rint¼0.0000), goodness-of-fit on F2 1.077, final
R
indices
11. (a) Yoshifuji, M.; Nagase, R.; Inamoto, N. Bull. Chem. Soc. Jpn. 1982, 55, 873–876;
(b) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211–5213.
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260–270.
13. Fukuhara, T.; Hasegawa, C.; Hara, S. Synthesis 2007, 10, 1528–1534.
14. Mathias, L. J.; Tullos, G. L. Polymer 1996, 37, 3771–3774.
15. Altomare, A.; Burla, M. C.; Camali, M.; Cascarano, M.; Giacovazzo, C.; Guagliardi,
A.; Polidori, G. J. Appl. Crystallogr. 1994, 27, 435–436.
[I>2
s
(I)]R1¼0.0732, wR2¼0.1824.
8. Client, J. C.; Balavoine, G. J. Organomet. Chem. 1991, 405, c29–c31.
9. (a) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434–442; (b) Daugulis, O.;
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