Copper-catalyzed oxidative amination of benzoxazoles via C-H and C-N bond activation: A new strategy for using tertiary amines as nitrogen group sources

Article abstract of DOI:10.1021/ol1030298

An efficient and conceptually new method for oxidative amination of azoles with tertiary amines via copper-catalyzed C-H and C-N bond activation has been developed. This protocol can be performed in the absence of external base and only requires atmospheric oxygen as oxidant. The catalyst system is very simple and efficient, which opens a new way for using tertiary amines as nitrogen group sources for C-N bond formation reactions.

Full text of DOI:10.1021/ol1030298

ORGANIC
LETTERS
2011
Vol. 13, No. 3
522-525
Copper-Catalyzed Oxidative Amination
of Benzoxazoles via C-H and C-N
Bond Activation: A New Strategy for
Using Tertiary Amines as Nitrogen
Group Sources
Shengmei Guo,† Bo Qian,† Yinjun Xie,† Chungu Xia,† and Hanmin Huang*,†,‡
State Key Laboratory for Oxo Synthesis and SelectiVe Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P. R. China, and
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou, 730000, P. R. China
hmhuang@licp.cas.cn
Received December 14, 2010
ABSTRACT
An efficient and conceptually new method for oxidative amination of azoles with tertiary amines via copper-catalyzed C-H and C-N bond
activation has been developed. This protocol can be performed in the absence of external base and only requires atmospheric oxygen as
oxidant. The catalyst system is very simple and efficient, which opens a new way for using tertiary amines as nitrogen group sources for C-N
bond formation reactions.
The transition-metal-catalyzed selective C-N bond formation
reaction through C-H bond activation is an efficient method
to facilitate the construction of complex amines.1 With
respect to the nitrogen group sources, primary amines,
secondary amines, chloroamines, and amides have been
successfully installed into the corresponding substrates via
C-H activation.2 Despite that remarkable success has been
achieved, to the best of our knowledge, tertiary amines used
as amino group sources for a direct amination reaction via
C-H and C-N bond activation have never been reported.
This limitation is probably due to difficulty in the cleavage
of the C-N bond as compared to other C-X bonds.3 Herein,
we report on a new and efficient procedure for aerobic
oxidative amination of azoles with tertiary amines as nitrogen
sources, which were catalyzed by a copper catalyst through
the cleavage of two C-H bonds and one C-N bond under
external-base-free conditions.
Given the importance of the azole motif in biological
medicinal chemistry and material chemistry, the direct C-H
functionalization of azole rings is of great interest.4,5 Among
(2) For selected examples: (a) Tsang, W. C. P.; Zheng, N.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Brasche, G.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (c) Inamoto, K.; Hasegawa,
C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147. (d) Thu, H.-Y.; Yu, W.-
Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (e) Liu, G.; Yin, G.;
Wu, L. Angew. Chem., Int. Ed. 2008, 47, 4733. (f) Li, B.-J.; Tian, S.-L.;
Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115. (g) Mei, T.-S.;
Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806. (h) Chen, X.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (i) Hamada,
T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (j) Fiori, K. W.;
Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562. (k) Liang, C.; Collet, F.;
Robert-Peillard, F.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem. Soc.
2008, 130, 343. (l) Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.;
Miura, M. J. Am. Chem. Soc. 2010, 132, 6900. (m) Zhao, H.; Wang, M.;
Sun, W.; Hong, M. AdV. Synth. Catal. 2010, 352, 1301.
† Lanzhou Institute of Chemical Physics.
‡ Lanzhou University.
(1) For reviews on C-H amination: (a) Armstrong, A.; Collins, J. Angew.
Chem., Int. Ed. 2010, 49, 2282. (b) Collet, F.; Dodd, R. H.; Dauban, P.
Chem. Commun. 2009, 5061. (c) Thansandote, P.; Lautens, M. Chem.sEur.
J. 2009, 15, 5874. (d) Dauban, P.; Dodd, R. H. Synlett 2003, 1571. (e)
Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
10.1021/ol1030298  2011 American Chemical Society
Published on Web 12/23/2010

the many types of C-H functionalization of azoles docu-
mented, the direct C-H amination of azoles pioneered by
Mori,6a Schreiber,6b Chang,6c and others2l,m provided a rapid
and straightforward access to the heteroarylamines. However,
all of the aforementioned methods inherently suffer from
harsh conditions such as high reaction temperature and use
of a stoichiometric amount of expensive organometallic
reagents and metal oxidant and a large amount of strong base
or acid. Therefore, further development for direct C-H
amination would be highly desired. The iminium-type
intermediate 2 was first reported by Murahashi and has
become one of the most useful active species for related
transformations.7 Li and co-workers developed the copper-
catalyzed cross-dehydrogenative coupling (CDC) of tertiary
amines with alkynes, active methylene, and nitromethane
(Scheme 1, A) by using this strategy.8 These elegant studies
have prompted us to envisage that, in the presence of
dioxygen-copper systems,9 the iminium-type species 2
would be generated from tertiary amine via C-H bond
cleavage. The reactive intermediate 2 might undergo C-N
bond cleavage via hydrolysis to produce the copper amide
Scheme 1. Proposed New Strategy for Oxidative Amination
6,10 which would react with azole 3 quickly. Thus the
directed C-H amination of azoles with tertiary amines would
be expected under the mild conditions (Scheme 1, B).
To test our hypothesis, the copper-catalyzed aerobic
oxidative C-H amination of benzoxazole 3a with Et3N 1a
as a nitrogen source was selected as a benchmark reaction.
As shown in Table 1, use of CuCl2 as a catalyst under 1 atm
(3) For catalytic C-N activation reaction: (a) Kuninobu, Y.; Nishi, M.;
Takai, K. Chem. Commun. 2010, 8860. (b) Kruger, K.; Tillack, A.; Beller,
M. ChemSusChem 2009, 2, 715. (c) Ueno, S.; Chatani, N.; Kakiuchi, F.
J. Am. Chem. Soc. 2007, 129, 6098. (d) Zou, B.; Jiang, H.-F.; Wang, Z.-Y.
Eur. J. Org. Chem. 2007, 4600. (e) Trzeciak, A. M.; Ciunik, Z.; Zioikowski,
J. J. Organometallics 2002, 21, 132. (f) Gandelman, M.; Milstein, D. Chem.
Commun. 2000, 1603. (g) Hosokawa, T.; Kamiike, T.; Murahashi, S.-I.;
Shimada, M.; Sugafuji, T. Tetrahedron Lett. 2002, 43, 9323. (h) Laine,
R. M.; Thomas, D. W.; Cary, L. W. J. Am. Chem. Soc. 1982, 104, 1763.
(4) For reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV.
2007, 107, 174. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.,
Int. Ed. 2009, 48, 9792. (c) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074. (d) Dudnik, A. S.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2010, 49, 2096.
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
acid (20 mol %)
none
t (°C)
yield (%)b
1
2
CuCl2
CuBr
80
80
29
23
34
<1
55
49
52
49
45
31
84
81
89
70
0
none
(5) For selected examples: (a) Do, H. Q.; Khan, R. M. K.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 15185. (b) Zhao, D.; Wang, W.; Yang, F.;
Lan, J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2009, 48, 3296.
(c) Do, H. Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (d) Canivet,
J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733. (e)
Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 4156.
(f) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed. 2009,
48, 201. (g) Huang, J.; Chan, J.; Chen, Y.; Broths, C.; Baucom, J. K. D.;
Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674. (h) Nakao,
Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. Angew. Chem., Int. Ed. 2010,
49, 4451. (i) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem.,
Int. Ed. 2010, 49, 2202.
3
4
5
6
7
8
9
10
11c
12
13
14d
15e
16
CuBr2
Cu(OAc)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
-
none
none
CH3CO2H
HCO2H
80
80
80
80
80
80
80
80
C6H5CO2H
(4-MeO)C6H4CO2H
(4-Me)C6H4CO2H
2-OHC6H4CO2H
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
80
100
120
120
120
120
(6) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178.
(c) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed.
2009, 48, 9127. (d) During the preparation of this manuscript, a report on
the C-H amination of azoles with secondary and primary amines was
published, but the yields are generally low: Kim, J. Y.; Cho, S. H.; Joseph,
J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899.
0
a General conditions: 3a (0.5 mmol), Et3N (1.0 mmol), 1,4-dioxane (1.0
mL), O2 (1 atm), 16 h. b Isolated yield. c CuBr2 (15 mol %). d CuBr2 (5
mol %). e In the Ar atmosphere.
(7) For reviews: (a) Murahashi, S.-I.; Hirano, T.; Yano, T. J. Am. Chem.
Soc. 1978, 100, 348. (b) North, M. Angew. Chem., Int. Ed. 2004, 43, 4126.
(c) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc.
2003, 125, 15312. (d) Murahashi, S.-I.; Komiya, N.; Terai, H. Angew. Chem.,
Int. Ed. 2005, 44, 6931.
(8) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2004, 126, 11810. (c) Li, Z.; Bohle, D. S.; Li, C.-J.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928.
of O2 at 80 °C yielded the desired amine 4aa in 29% yield
(Table 1, entry 1) and no dimer of benzoxazole was observed,
which indicated that the desired C-H amination involving
C-H and C-N bond cleavage was indeed possible albeit
in low yield. Other copper sources, including CuBr, CuBr2,
and Cu(OAc)2, were also tested, and the results demonstrated
that CuBr2 was the best choose (Table 1, entries 1-4). Other
commonly used metal salts such as Ag(I) salts, Pd(OAc)2,
(9) For reviews on copper-dioxygen catalytic systems: (a) Lewis, E. A.;
Tolman, W. B. Chem. ReV. 2004, 104, 1047. (b) Mirica, L. M.; Otten-
waelder, X.; Stack, T. D. P. Chem. ReV. 2004, 104, 1013. (c) Prigge, S. T.;
Eipper, B. A.; Mains, R. E.; Amzel, L. M. Science 2004, 304, 864. (d)
Nam, W. Acc. Chem. Res. 2007, 40, 465. For selected examples: (a)
Kunishita, A.; Ishimaru, H.; Nakashima, S.; Ogura, T.; Itoh, S. J. Am. Chem.
Soc. 2008, 130, 4244. (b) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 833. (c) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am.
Chem. Soc. 2009, 131, 5044. (d) Zhang, C.; Jiao, N. J. Am. Chem. Soc.
2010, 132, 28. (e) Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49,
6174.
(10) Tian, J.-S.; Loh, T.-P. Angew. Chem., Int. Ed. 2010, 49, 8417.
Org. Lett., Vol. 13, No. 3, 2011
523

and Ni(II) salts proved to be either less effective or totally
ineffective (see Supporting Information). The addition of 20
mol % CH3COOH greatly improved the reaction efficacy,
and 4aa was obtained in 55% yield (Table 1, entry 5). Other
acids such as HCOOH, C6H5COOH, and salicylic acid were
less effective than CH3COOH (Table 1, entries 6-10).
Increasing the catalyst loading (from 10 mol % to 15 mol
%) or temperature (from 80 to 120 °C) could enhance the
reaction efficacy. High yields up to 84% with 15 mol %
CuBr2 as a catalyst at 80 °C and 89% yield with 10 mol %
catalyst loading at 120 °C were obtained, respectively. The
catalyst loading could be decreased to 5 mol % and still
provide good yields at high temperature. In addition, in the
absence of a copper source or in the presence of O2-free
conditions, no aminated product was observed under the
same reaction conditions (Table 1, entries 15 and 16).
Under the optimized conditions, the scope of this oxidative
C-H amination reaction was investigated with a variety of
tertiary amines. As shown in Table 2, almost all alkyl tertiary
suggesting that R-H is essential for the C-H amination under
these conditions. In addition to simple alkyl amines, the
unsaturated triallyl amine 1h also participated in the oxidative
C-H amination reaction to give the corresponding N,N-
diallyl benzoxazole 4ah (Table 2, entry 8). The bulky
diisopropylethyl amine 1i containing two kinds of R-H
afforded two types of products, 4ai and 4ai′, in an almost
1:1 ratio, which indicated that the sterically less hindered
alkyl group is much more facile for cleavage. Similarly, two
kinds of aminated products, 4aa and 4aj, were obtained in
the reaction of N-benzyl-N-ethylethanamine 1j, where the
C-N bond cleavage took place at the two cleavable C-N
bonds, respectively. However, the morpholine derived tertiary
amines 1k and 1l reacted exclusively at their exocyclic C-N
bond to give cyclic amine 4ak (Table 2, entries 11 and 12).
The same regioselectivity was also observed in the reaction
of benzoxazole with 1m to exclusively cleave the exocyclic
C-N bond giving the valuable 4am in high yield (Table 2,
entry 13). Whereas the reaction had been performed at 120
°C to rapidly obtain a cleaner process, it was found that a
15% mol amount of CuBr2 at 80 °C was sufficient to provide
the desired product in almost the same yields.
Table 2. Substrate Scope of Aminesa
Next, the scope of this reaction was investigated with
respect to azole under the same conditions as those shown
in Table 2. Some representative results are summarized in
Scheme 2. The reactions of 6-, 4-, and 5-methylbenzoxazoles
Scheme 2.
Substrate Scope of Azolesa
a (a) The reaction conditions: 3 (0.5 mmol), 1 (1.0 mmol), CuBr2 (10
mol %), CH3COOH (20 mol %), in 1,4-dioxane (1 mL) under 1 atm of O2,
120 °C, 16 h; isolated yield; the data in parentheses are obtianed at 80 °C
with 15 mol % CuBr2 in 30 h. (b) 100 mol % CuBr2 was used. (c) With 2i
as amine source. (d) With 20 mol % PhCOOH as an additive.
a The reaction conditions: 3a (0.5 mmol), 1 (1.0 mmol), CuBr2 (10 mol
%), CH3COOH (20 mol %), in 1,4-dioxane (1 mL) under 1 atm of O2, 120
°C, 16 h. b Isolated yield. c CuBr2 (15 mol %), 80 °C.
with Et3N took place smoothly to furnish the desired amines
4ba, 4ca, and 4da, which were isolated in 82-88% yield,
and no significant rate difference was observed. Furthermore,
the sterically more demanding product 4ha was also obtained
in 87% yield. These results suggest that this reaction is not
sensitive to the steric hindrance in the benzene ring of azole.
The chloro and bromo group could survive the reaction
amines 1a-1f, bearing R-H adjacent to the nitrogen atom,
provided the desired products 4aa-4af in 54-92% yield
(Table 2, entries 1-6). No product formation was observed
with triphenylamine 1g as an amino group source, in which
no C-H bond R to the nitrogen atom is contained, thus
524
Org. Lett., Vol. 13, No. 3, 2011

conditions to give the corresponding functionalized amine
products such as 4ea, 4fa, and 4la in excellent yield (up to
99% yield). The 5-arylated benzoxazole derivative could be
used in this oxidative C-H amination reaction to give the
functionalized product 4ga in almost quantitative yield.
However, in the case of 5-nitro-substituted benzoxazole,
although the expected oxidative C-H amination product 4ia
could be obtained in 36% yield, stoichiometric CuBr2 was
required. In contrast to benzoxazoles, 2-phenyl-1,3,4-oxa-
diazole afforded the corresponding amine 4ja in 30% yield,
while benzothiazole afforded the desired product 4ki in 10%
yield, the lower reactivity of these substrates observed here
is probably due to their weaker acidity.
Scheme 3
.
Proposed Reaction Pathway for the Cu-Catalyzed
Oxidative C-H Amination
To gain some insight into the mechanism of the present
C-H amination process, we first conducted the reaction on
gram scale with 3a and 1l as reactants which afforded the
desired aminated product 4ak in 75% yield and inherently
together with the benzaldehyde in 87% yield (based on 3a,
see Supporting Information). The concomitant isolation of
benzaldehyde in amounts a little more than that of the desired
amination product 4ak might indicate that C-N bond
cleavage most likely takes place prior to the new C-N bond
formation step.3a Radical scavengers, such as TEMPO and
1,1-diphenylethylene, were employed in the standard reac-
tion, and the desired product 4aa was still obtained in 62%
and 81% yields, respectively (see Supporting Information).
This result suggested that a free radical process is not a
requirement for the present reaction. To investigate the origin
of the aldehyde and the transformation of the resected H
atoms from the tertiary amine and azole, an isotopic labeling
experiment with 18O2 was conducted. The results demon-
strated clearly that the resected H atoms transformed into
water and the oxygen of aldehyde was from molecular O2.
Further isotopic labeling experiments with 18O2 and H218O
suggested the oxygen of aldehyde directly originated from
water and the produced water of the reaction participated in
the C-N bond cleavage event for hydrolysis of the iminium-
type intermediate. The kinetic isotope effects (KIEs) for both
coupling partners were determined for investigation in which
one of the C-H bond cleavage processes was involved in
the rate-limiting step (see Supporting Information). An
intermolecular competition reaction between 5-methylben-
zoxazole and 2-deuterated-5-methylbenzoxazole showed a
KIE of 1.4, suggesting that C-H cleavage of the azole is
not involved in the rate-limiting step. However, the primary
KIE of 2.7 was observed for 4-benzylmorpholine, which
indicated that C-H cleavage of the tertiary amines is
significant with respect to the rate-limiting step.
of the copper salt and molecular oxygen.9 The high Lewis
acidic copper species coordinates to the tertiary amine and
reacts with it to give the iminium-type intermediate A by
elimination of water which was assisted by CH3COOH.
Iminium-type intermediate A is then hydrolyzed to be
converted into the key intermediate B by elimination of
aldehyde.9 B would coordinate to azole to yield C, and its
subsequent deprotonation/rearrangement would afford D and
regenerate CH3COOH followed by reductive elimination to
form the desired product and regenerate the copper catalyst
to complete the catalytic cycle. The results of KIE experiment
indicate that the C-N bond cleavage is slow, which is
beneficial to form a reactive copper amide B.11
In summary, we have established an efficient and con-
ceptually new strategy for oxidative C-H and C-N bond
activation, which provides a new method for C-H amination
of azoles with tertiary amines as nitrogen group sources. This
reaction can be performed in the absence of an external base
under mild conditions and only requires atmospheric oxygen
as an oxidant. The success of the present studies not only
provides a powerful method for the construction of new C-H
amination reactions but also suggests a new strategy for C-N
bond activation.
Acknowledgment. Financial support provided by the
National Natural Science Foundation of China (20802085,
20625308) and Chinese Academy of Sciences are gratefully
acknowledged.
Supporting Information Available: Experimental details
and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
On the basis of the results that we obtained here and
previously,10 a plausible mechanism for the present process
is proposed as shown in Scheme 3. Initially, the copper
catalyst is oxidized by oxygen to form [LnCun+1] composed
OL1030298
(11) Giri, R.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 15860.
Org. Lett., Vol. 13, No. 3, 2011
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