Amination of the ortho C-H bonds by the Cu(OAc)2-mediated reaction of 2-phenylpyridines with anilines

Article abstract of DOI:10.1246/cl.2006.842

The reaction of 2-phenylpyridines with anilines in the presence of Cu(OAc)₂ as a promoter results in selective mono-amination of the ortho C-H bonds in 2-phenylpyridines to give amine derivatives in high yields per the conversion. This is the r

Full text of DOI:10.1246/cl.2006.842

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42
Chemistry Letters Vol.35, No.8 (2006)
Amination of the Ortho C–H Bonds by the Cu(OAc) -mediated Reaction
2
of 2-Phenylpyridines with Anilines
Ã
Takeshi Uemura, Shinya Imoto, and Naoto Chatani
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
Received May 17, 2006; CL-060585; E-mail: chatani@chem.eng.osaka-u.ac.jp)
Table 1. Ortho-amination of 2-phenylpyridine (1) with aniline
(
The reaction of 2-phenylpyridines with anilines in the pres-
ence of Cu(OAc)2 as a promoter results in selective mono-ami-
nation of the ortho C–H bonds in 2-phenylpyridines to give
amine derivatives in high yields per the conversion. This is the
rare example of the functionalization of C–H bonds to C–N
bonds.
N
N
+
PhNH2
mmol
Mesitylene 1 mL
160 °C, 20 h
1
NHPh
1
(0.5 mmol)
2
Entry
Cu(OAc)2
1 mmol
2/%
Recovered 1/%
1
2
3
4
27
55
47
42
65
44
50
48
0.6 mmol
0.6 mmol
2
Development of transition metal-catalyzed selective func-
tionalization of C–H bonds is a challenge of intensive current
2 (2 h)
3 (2 h)
0
.6 mmol
1
interest. A chelation methodology in which ketone, ester, pyri-
dine, and oxazoline function as the directing group is now
recognized as one of the most promising methods for the func-
rior to other Cu salts, such as CuCl, CuI, Cu(OTf), CuBr2, CuO,
and Cu(OCOCF3)2 as the promoter for the amination. The
reaction of 2-phenylpyridine (1, 0.5 mmol), aniline (1 mmol) in
the presence of Cu(OAc)2 (1 mmol) in mesitylene (1 mL) at
2
tionalization of not only C–H bonds but also other bonds, such
3
4
5
6
as C–O, C–C, C–F, and O–H bonds. Currently, most of the
examples involving functionalization of C–H bonds by the
utilization of the chelation methodology result in the formation
of C–C bonds. However, less attention has been focused on
the formation of carbon–heteroatom bonds from C–H bonds
until now, compared with extensively studied C–C bond forma-
tion reactions. Quite recently, some reports involving such a
formation of carbon–heteroatom from C–H bonds have appeared
ꢀ
160 C for 20 h gave amination product 2 in 27% yield, 1 being
recovered in 65% yield (Entry 1 in Table 1). The yield of 2 was
improved when a two-batch-wise addition of Cu(OAc)2 was em-
ployed (Entry 2). A comparable yield was obtained when the re-
action was carried out for 2 h (Entry 3). However, a three-batch-
wise addition was not effective (Entry 4). Although the conver-
sion was not high, the reaction system was clean and no byprod-
ucts were formed. It was found that the inhibition by the product
is responsible for the incomplete conversion. In fact, the addition
of product in the reaction system retarded the reaction.
2
in literatures. We found that silylation of sp and benzylic C–H
7
bonds with hydrosilanes is achieved by ruthenium complexes.
Sanford reported on the formation of C–O and C–halogen bonds
8
via a Pd(IV) intermediates. Yu et al. also reported the Pd(II)-
3
The results on the reaction of some 2-arylpyridines are
shown in Table 2. The electronic nature and position of substitu-
ents on the phenyl ring had a significant effect on the efficiency
catalyzed ionidation of sp C–H bonds using I2 and PhI(OAc)2
as oxidants.9
The formation of C–N bonds has been the subject of intense
studies. The majority of the formation of C–N bonds involves
a coupling of aryl halides with amines mediated by copper or
Table 2. Ortho-amination of 2-phenylpyridines with anilinea
Yield/%b
2
-Arylpyridine
N
Product
1
0
palladium complexes. Few examples of the transformation of
C–H bonds to C–N bonds by utilizing a chelation strategy exists
thus far. Recently, Buchwald et al. reported the formation of
intramolecular C–N bond via a C–H bond activation of 2-
phenylbenzacetanilides catalyzed by Pd(II) species to produce
acetocarbazoles.11 We now wish to report on the chelation-
assisted intermolecular amination of the ortho C–H bonds of
R = Me
CF3
OMe
3
43 (57)
30 (67)
40 (45)
N
4
5
R
R
R
R
NHPh
R = Me
6
7
17 (65)
14 (80)
trace
N
N
CF3
1
2
OMe
NH
Ph
2
-phenylpyridines with anilines mediated by Cu(OAc)2.
Our initial idea involved the ortho-palladation via an elec-
R
R
R = Me
trace
trophilic substitution of Pd(II) complexes with 2-phenylpyri-
dines, reaction with amines, reductive elimination, followed by
reoxidation of the resulting Pd(0) to Pd(II) by Cu(II). When 2-
phenylpyridine (1) was treated with aniline (1 mmol) in the pres-
N
CF3
N
trace
OMe
8
9
40 (46)
NH
Ph
ꢀ
ence of PdCl2 and Cu(OAc)2 in toluene at 160 C for 20 h, a trace
amount of ortho-amination product 2 was formed. Encouraged
by this result, much effort has been made to optimize the reaction
conditions by using alternate directing group and changing tran-
sition metals, amines, solvents, and temperatures employed.
Finally, We were pleased to find that Cu(OAc)2 alone is active
in the amination of C–H bonds as a promoter. Cu(OAc)2 is supe-
N
N
27 (67)
NH
Ph
a
Reaction conditions: substrate (0.5 mmol), aniline (1 mmol),
ꢀ
Cu(OAc) (0.6 mmol  2), mesitylene (1 mL), 160 C for 2 h.
2
b
A number in parenthesis is the yield of the recovered substrate.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.8 (2006)
843
Table 3. Ortho-amination of 2-phenylpyridine (1) with
a
In summary, we demonstrated the chelation-assisted inter-
molecular amination of the ortho C–H bonds in 2-phenylpyri-
dines mediated by copper salt. While the reaction requires
stoichiometric amounts of Cu(OAc)2 and the conversion is
not high, the reaction does not require expensive metals and
ancillary ligands, and the yields per the conversion are quite
high, indicating no byproduct formation.
anilines
Yield/%b
Aniline
Product
NH2
R = Me
tBu
N
10 41 (50)
11 30 (67)
12 24 (32)
R
NH
CF3
R
This work was supported by Kansai Research Foundation
for Technology Promotion.
NH2
N
1
3
31 (68)
References and Notes
NH
Me
1
For recent reviews, see: F. Kakiuchi, S. Murai, Acc. Chem. Res.
002, 35, 826; M. Miura, M. Nomura, Top. Curr. Chem. 2002,
219, 211; F. Kakiuchi, N. Chatani, Adv. Synth. Catal. 2003, 345,
077.
2
Me
1
NH2
R
2
For recent examples, see: J. H. Yoon, T. J. Park, J. H. Lee, J. Yoo,
C.-H. Jun, Org. Lett. 2005, 7, 2889; R. K. Thalji, K. A. Ahrendt,
R. G. Bergman, J. A. Ellman, J. Org. Chem. 2005, 70, 6775; F.
Kakiuchi, Y. Matsuura, S. Kan, N. Chatani, J. Am. Chem. Soc.
N
R = Me
CF3
14 28 (67)
15 49 (32)
NH
2
005, 127, 5936; V. G. Zaitsev, D. Shabashov, O. Daugulis,
J. Am. Chem. Soc. 2005, 127, 13154; Y. Kuninobu, A. Kawata,
K. Takai, J. Am. Chem. Soc. 2005, 127, 13498; X. Chen, J.-J.
Li, X.-S. Hao, C. E. Goodhue, J.-Q. Yu, J. Am. Chem. Soc.
2006, 128, 78.
F. Kakiuchi, M. Usui, S. Ueno, N. Chatani, S. Murai, J. Am. Chem.
Soc. 2004, 126, 2706.
N. Chatani, Y. Ie, F. Kakiuchi, S. Murai, J. Am. Chem. Soc. 1999,
R
a
Reaction conditions: substrate (0.5 mmol), aniline (1 mmol),
Cu(OAc)2 (0.6 mmol  2), mesitylene (1 mL), 160 C for 2 h.
ꢀ
b
A number in parenthesis is the yield of the recovered substrate.
3
4
of the reaction. The presence of a substituent, such as a methyl or
trifluoromethyl group, on the ortho position retarded the reac-
tion, however the presence of methoxy group did not affect the
efficiency of the reaction.
The effect of structures of anilines was next examined
Table 3). Unlike the effect of a substituent on the phenyl ring
in 2-arylpyridines, as shown in Table 2, the significant steric
effect of the ortho substituent on aniline was not observed even
in the case of tert-butyl group. The use of methoxy-substituted
aniline gave no reaction, irrespective of the position of the
methoxy group. Methoxy-substituted anilines were converted
to unisolable products owing to electron transfer from anilines
1
1
21, 8645; C.-H. Jun, H. Lee, S.-G. Lim, J. Am. Chem. Soc. 2001,
23, 751.
5
6
Y. Ishii, N. Chatani, S. Yorimitsu, S. Murai, Chem. Lett. 1998,
157.
K. Yokota, H. Tatamidani, Y. Fukumoto, N. Chatani, Org. Lett.
2003, 5, 4329; S. Inoue, K. Yokota, H. Tatamidani, Y. Fukumoto,
N. Chatani, Org. Lett., 2006, 8, 2519.
(
7
8
F. Kakiuchi, K. Igi, M. Matsumoto, N. Chatani, S. Murai, Chem.
Lett. 2001, 422.
A. R. Dick, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2004,
1
26, 2300; L. V. Desai, K. L. Hull, M. S. Sanford, J. Am. Chem.
Soc. 2004, 126, 9542; D. Kalyani, M. S. Sanford, Org. Lett.
2005, 7, 4149.
R. Giri, X. Chen, J.-Q. Yu, Angew. Chem., Int. Ed. 2005, 44, 2112.
9
to copper(II) salt.
The reaction mechanism is not clear at the present time.13
10 A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 131;
S. V. Ley, A. W. Thomas, Angew. Chem., Int. Ed. 2003, 42, 5400.
One can propose that selective acetoxylation by Cu(OAc)2 takes
place at the ortho C–H bonds and then the resulting acetoxyla-
tion product undergoes the Cu(OAc)2-promoted amination
under the reaction conditions employed. This possibility can
be excluded by the following experiment. When independently
prepared acetate 16 was exposed under reaction conditions, 16
underwent aminolysis to give 17 in 47% yield, but no amination
product 2 was observed (Scheme 1).
1
1 W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc.
005, 127, 14560.
2
1
2 After our work was finished, we found Yu’s work on the Cu(II)-
catalyzed functionalization of C–H bonds in 2-phenylpyridines ap-
pears in ASAP (released on May 6, 2006) of J. Am. Chem. Soc.
While their major work is chlorination at ortho C–H bonds in 2-
phenylpyridines catalyzed by CuCl2, they also reported one
example of amination of C–H bonds using TsNH2 in the presence
of a stoichiometric amount of Cu(OAc)2. X. Chen, X.-S. Hao,
C. E. Goodhue, J.-Q. Yu, J. Am. Chem. Soc. 2006, 128, 6790.
3 One possibility is the intermediacy of unusual cyclometalated Cu
complexes, which are generated from 1 and Cu(OAc)2. An alter-
native mechanism involves SET process from the benzene ring
of 1-coordinated Cu complexes. In both cases, the coordination
of the pyridine in 1 is required for the reaction to proceed. In fact,
the presence of a methyl group at the 6-position of the pyridine
ring resulted in no reaction.
1
Cu(OAc)2
N
N
+
PhNH2
1 mmol
mesitylene 1 mL
160 °C, 20 h
OAc
OH
17 47%
16
Scheme 1.
Published on the web (Advance View) June 27, 2006; doi:10.1246/cl.2006.842