Cu(acac)2 catalyzed oxidative C-H bond amination of azoles with amines under base-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.09.064

This work reports a simple and efficient methodology for oxidative C-H bond amination of azoles with aromatic/aliphatic amines using copper-bis- acetylacetonate complex catalyst. The catalyst works very well in the absence of external acid or base and requires only molecular oxygen as an oxidant. The methodology is applicable for the oxidative C-H bond amination of various azoles with different types of aromatic/aliphatic amines for the synthesis of various aminoheterocycles with good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.09.064

Tetrahedron Letters 53 (2012) 6500–6503
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu(acac)2 catalyzed oxidative C–H bond amination of azoles with amines
under base-free conditions
⇑
Yogesh S. Wagh, Bhalchandra M. Bhanage
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This work reports a simple and efficient methodology for oxidative C–H bond amination of azoles with
aromatic/aliphatic amines using copper-bis-acetylacetonate complex catalyst. The catalyst works very
well in the absence of external acid or base and requires only molecular oxygen as an oxidant. The meth-
odology is applicable for the oxidative C–H bond amination of various azoles with different types of aro-
matic/aliphatic amines for the synthesis of various aminoheterocycles with good to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 7 August 2012
Revised 13 September 2012
Accepted 15 September 2012
Available online 2 October 2012
Keywords:
Aminoheterocycles
Oxidative amination
C–H activation
Homogeneous catalysis
Azoles
Transition-metal-catalyzed C–N bond formation reactions of
heteroarenes are very important transformations in organic syn-
thesis. Aminoheterocycles are widely applicable in biological sys-
tems, pharmaceuticals, and material sciences.1 They can be
synthesized via palladium-catalyzed Buchwald–Hartwig coupling2
and copper-catalyzed Ullmann and Goldberg coupling3 reactions.
Although considerable progress has been made in this direction,
still there are some disadvantages, such as requirement of high
temperature, longer reaction time, requirement of ligands, and
non-economic effects. Hence, to develop greener and more simpli-
fied methods, direct C–H bond amination of heteroarenes has been
reported by several researchers.4,5 The transition-metal-catalyzed
selective C–H bond functionalization reactions of arenes and het-
eroarenes have significant importance in organic synthesis because
of its high atom efficiency compared to related cross-coupling
reactions using organometallic compounds. In particular, the oxi-
dative C–H bond amination reaction of heteroarenes for the syn-
thesis of various aminoheterocycles is important because of its
wide range of applications in the synthesis of biologically active
compounds and organic intermediates.6,7 Selective oxidative func-
tionalization of C–H bonds in heteroarenes with amines is one of
the challenging transformations.
Fe(III).8 The oxidative C–H bond amination of benzoxazoles has
been explored satisfactorily and successfully at metal-free condi-
tions.9 Although there are several reports on oxidative C–H bond
amination of benzoxazoles, the reported protocols have some
drawbacks such as the use of stoichiometric amount of carboxylic
acid as a promoter and non-greener peroxide oxidants. Oxidative
C–H bond amination of other azoles is comparatively more chal-
lenging and was not well studied. In this direction, Mori and co-
workers for the first time developed a copper-catalyzed oxidative
C–H bond amination of azoles in the presence of phosphine ligand
and stoichiometric amount of base under oxygen atmosphere.10
However, the use of stoichiometric amount of base and phosphine
ligand is not attractive as phosphines are highly susceptible for
oxidation in the presence of molecular oxygen.
In this context, herein we describe a simple, efficient, and well
defined copper-bis-acetylacetonate [Cu(acac)2] catalyzed method-
ology for direct oxidative C–H bond amination of azoles under
base-free and any additional ligand-free conditions (Scheme 1).11
High solubility of Cu(acac)2 complex in organic solvents, indefinite
shelf life, stability toward air, and compatibility with various
In this direction various research groups have reported oxida-
tive C–H bond amination reactions of azoles using various transi-
tion metal catalysts such as Cu(II), Ag(I), Co(II), Mn(II), and
R1
R1
R2
N
X
N
X
Cu(acac)2, O2
xylene, 140°C
N
H
+
HN
R2
3
1
2
⇑
Corresponding author. Tel.: +91 22 33612601; fax: +91 22 33611020.
E-mail addresses: bhalchandra_bhanage@yahoo.com, bm.bhanage@gmail.com
X= S/O/NR
(B.M. Bhanage).
Scheme 1. Cu(acac)2 catalyzed oxidative amination of azoles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.064

Y. S. Wagh, B. M. Bhanage / Tetrahedron Letters 53 (2012) 6500–6503
6501
Table 1
Table 2
Oxidative C–H bond amination reaction of benzothiazole (1) with N-methylaniline
Optimization of oxidative C–H bond amination reactiona
(2a)a
Entry
Solvent
Cu(acac)2
(mol %)
Temperature
Time
(h)
GC yield
(°C)
N
S
N
S
Cu catalyst
Influence of solvent
H
+
N
1
2
3
4
5
Xylene
Toluene
Cyclohexane
Dioxane
Acetonitrile
10
10
10
10
10
140
110
80
100
80
24
24
24
24
24
70
30
02
tr
HN
xylene, 140°C
Ph
Ph
2a
1
3
tr
Entry
Copper catalyst
(10 mol %)
Oxidant
Base
(2 mmol)
GC yield
(%)
Influence of temperature
6
7
8
Xylene
Xylene
Xylene
10
10
10
110
120
140
24
24
24
28
46
70
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
Cu(TMHD)2
CuBr2
Cu(acac)2
Cu(acac)2
Cu(acac)2
O2
O2
O2
O2
O2
O2
Air
—
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
—
54
34
72
55
22
70
40
tr
Influence of time
9
10
11
12
Xylene
Xylene
Xylene
Xylene
10
10
10
10
140
140
140
140
12
16
20
30
40
62
70
71
—
—
Influence of catalyst loading
a
Reaction condition: 1 (1 mmol), 2a (2 mmol), xylene (5 mL) at 140 °C, 24 h.
13
14
15
16
Xylene
Xylene
Xylene
Xylene
5
140
140
140
140
20
20
20
20
45
70
79
85
10
15
20
hindered and functionalized amines make it an ideal catalyst for
such type of reactions. Molecular oxygen is successfully utilized
as a green oxidant. It is an ideal oxidant because of its easy avail-
ability, low cost, and absence of toxic side-products in the reaction
mixture.
a
Reaction condition: 1 (1 mmol), 2a (2 mmol), O2 gas (bubbling), solvent (5 mL).
tures ranging from 110–140 °C (Table 2, entries 6–8), in which
140 °C reflects to be the optimum reaction temperature (Table 2,
entry 8). The time of the reaction was also optimized (Table 2, en-
tries 9–12) and a maximum yield of product 3 was obtained within
20 h (Table 2, entry 11). The effect of catalyst loadings ranging
from 5–20 mol % was studied and it can be seen that an increase
in catalyst loading up to 20 mol % led to a remarkable increase in
the yield of the desired product 3 that is up to 85% (Table 2, entry
16). Thus, the optimized reaction conditions are 1 (1 mmol), 2a
(2 mmol), Cu(acac)2 (20 mol %) in xylene (5 mL) under continuous
bubbling of O2 into the reaction mixture at 140 °C for 20 h.
To study the scope and generality of the present protocol, vari-
ous azoles such as benzothiazole, benzoxazole, 4,5-dimethylthia-
zole, and N-methylbenzimidazole were studied for the oxidative
C–H bond amination reaction with aromatic amine, that is
N-methylaniline under the above optimized reaction conditions
(Table 3, entries 1–4). The reactions were monitored on GC and
the respective aminoheterocycles were isolated with good to
excellent yield (82–85%) after complete consumption of starting
azoles.
The reactions of benzoxazoles (4a) with various aliphatic cyclic
and acyclic amines were performed under the optimized reaction
conditions (Table 3, entries 4–12). Cyclic aliphatic amines such as
morpholine, piperidine, pyrrolidine, N-methylpiperazine, N-acetyl-
piperazine, and 1,2,3,4-tetrahydroisoquinoline were treated with
4a. All these cyclic aliphatic amines reacted smoothly with 4a
and gave good to excellent yields of corresponding aminobenzox-
azoles (Table 3, entries 5–10). Further, 4a was reacted with
aliphatic acyclic secondary amines such as dibutylamine and
N-methylbenzylamine (Table 3, entries 11–12).
Benzothiazole (1) and N-methylaniline (2a) were chosen as
model substrates for the purpose of optimization of reaction condi-
tions for oxidative C–H bond amination reaction. Initially, various
copper catalysts such as Cu(OAc)2, Cu(OTf)2, Cu(acac)2, Cu(TMHD)2
[Copper-bis(2,2,6,6-tetramethyl-3,5-heptanedionate)], and CuBr2
were screened for the C–H bond amination reaction of 1 (1 mmol)
and 2a (2 mmol) using sodium acetate (2 mmol) as a base in xylene
solvent at 140 °C with continuous bubbling of oxygen into the
reaction mixture (Table 1, entries 1–5). The reaction in the pres-
ence of Cu(OAc)2 afforded 54% yield of the amination product 3
(Table 1, entry 1). Further, Cu(OTf)2, Cu(acac)2, Cu(TMHD)2, and
CuBr2 were screened under the same reaction conditions (Table 1,
entries 2–5). It has been observed that, Cu(acac)2 has shown a good
catalytic activity among all the above catalysts screened and fur-
nished 72% yield of 3 (Table 1, entry 3). To check the role of base
for oxidative C–H bond amination reaction, the reaction of 1 with
2a was performed in the absence of sodium acetate (Table 1, entry
6). To our surprise, we observed 70% yield of 3 in the absence of
base. Further, the reaction was performed under air bubbling into
the reaction mixture, however, reaction proceeds sluggishly with
decrease in yield up to 40% of product 3 (Table 1, entry 7). Only
a trace amount of product 3 was observed when the reaction
was performed without any oxidant (Table 1, entry 8).
Furthermore, we have examined the influence of various reac-
tion parameters like solvent, temperature, time, and catalyst load-
ing (Table 2). Initially, the influence of various organic solvents
with a different polarity was studied for oxidative C–H bond ami-
nation reaction (Table 2, entries 1–5). Xylene was found to be the
best solvent among all the solvents screened and provided 70%
yield of the desired product 3 (Table 2, entry 1). Only 30% yield
of product 3 was observed when toluene was used as a solvent
(Table 2, entry 2). However, other low boiling solvents were not
effective and gave only traces of desired product 3 (Table 2, entries
3–5). The reaction requires optimized reaction temperature of
140 °C and many of these solvents were not able to reach that un-
der reflux conditions. It can be concluded that aromatic solvents
are necessary for this reaction as other types of solvents were
not able to get the products even in a trace amount even at
80 °C. The reactions were performed at various reaction tempera-
It was observed that, both the aliphatic acyclic secondary
amines tolerated very well under the present optimized reaction
conditions, yielded 78% and 81% respective aminobenzoxazoles.
Later, 5-methylbenzoxazole (4b) was reacted with morpholine
and piperidine, it showed that, respective aminobenzoxazoles 5j
and 5k were obtained in moderate to good yields (Table 3, entries
13–14).
In conclusion, we have developed Cu(acac)2 catalyzed base-free
protocol for the oxidative C–H bond amination of azoles using
molecular oxygen as an oxidant. Present protocol is simple, effi-

6502
Y. S. Wagh, B. M. Bhanage / Tetrahedron Letters 53 (2012) 6500–6503
Table 3
Oxidative C–H bond amination of azoles with aminesa
Entry
1
Azole
Amine (2)
Product (3)
Time (h)
20
Yieldb (%)
85
N
S
N
HN
Ph
2a
N
N
N
S
Ph
Ph
1
3
N
O
N
2
3
2a
2a
2a
18
20
88
84
O
4a
5a
N
N
N
N
Ph
7
6
N
S
N
N
4
5
6
7
8
9
20
12
14
12
12
14
82
90
88
88
85
82
S
Ph
8
9
N
O
HN
O
N
O
4a
2b
5b
5c
5d
5e
5f
N
O
HN
N
N
4a
4a
4a
4a
2c
O
N
HN
2d
N
O
HN
N
N
N
N
N
2e
O
O
N
O
HN
N
2f
O
N
N
NH
10
11
4a
15
15
84
78
2g
5g
nBu
nBu
nBu
nBu
O
N
HN
N
4a
4a
2h
HN
2i
5h
5i
O
N
N
12
13
14
16
14
14
81
86
81
Ph
Ph
O
N
O
N
N
N
O
2b
2c
4b
5j
O
N
4b
5k
a
Reaction condition: azole (1 mmol), amine (2 mmol), Cu(acac)2 (20 mol %), O2 gas (bubbling), xylene (5 mL) at 140 °C.
Isolated yield.
b
cient, and applicable for C–H bond amination of various azoles
with different aromatic as well as aliphatic amines. Varieties of
aminoheterocycles have been successfully synthesized with good
to excellent yield under the present reaction condition.
References and notes
1. (a) Amino Group Chemistry from Synthesis to the Life Sciences; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2008; (b) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2,
284–287; (c) Seregin, I. V.; Gevorgan, V. Chem. Soc. Rev. 2007, 36, 1173–1193.
and references therein.
2. (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209; (b) Surry, D.
S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–6361; (c) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534–1544.
Acknowledgment
3. (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079; (b) Kwong, F. Y.;
Buchwald, S. L. Org. Lett. 2003, 5, 793–796; (c) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400–5449; (d) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003,
The author (Y.S.W.) is greatly thankful to the Council of Scien-
tific and Industrial Research (CSIR), India for providing fellowship.

Y. S. Wagh, B. M. Bhanage / Tetrahedron Letters 53 (2012) 6500–6503
6503
5, 2453–2455; (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054–3131; (f) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48,
1114–1116.
removed under reduced pressure. The reaction mixture was analyzed using gas
chromatography (Perkin Elmer, Clarus 400) equipped with a flame ionization
detector (FID) and capillary column. The crude product was purified by column
chromatography (silica gel, 100–200 mesh; petroleum ether/ethyl acetate,
90:10) to afford pure products. All the prepared compounds were confirmed by
comparing with their authentic samples and were characterized by GC–MS
(Shimadzu QP 2010), 1H NMR (Varian 500 MHz).
N-Methyl-N-phenylbenzothiazol-2-amine (3, Table 3, entry 1): GC–MS (EI,
70 eV): m/z (%) = 240 (100), 239 (89), 106 (40), 77 (23).
N-Methyl-N-phenylbenzoxazol-2-amine (5a, Table 3, entry 2): GC–MS (EI,
70 eV): m/z (%) = 224 (100), 223 (39), 106 (41), 77 (30).
N,1-Dimethyl-N-phenyl-1H-benzoimidazol-2-amine (7, Table 3, entry 3): GC–MS
(EI, 70 eV): m/z (%) = 237 (100), 236 (70), 91 (15), 77 (22).
N,4,5-Trimethyl-N-phenylthiazol-2-amine (9, Table 3, entry 4): GC–MS (EI,
70 eV): m/z (%) = 218 (100), 217 (47), 77 (24), 51 (12).
2-Morpholinobenzoxazole (5b, Table 3, entry 5): GC–MS (EI, 70 eV): m/z
(%) = 204 (79), 147 (100), 119 (29). 1H NMR (500 MHz, CDCl3, 25 °C): d = 7.37
(d, J = 7.0 Hz, 1 H), 7.26 (d, 1 H, J = 6.5 Hz), 7.18 (m, 1 H), 7.04 (m, 1 H), 3.82 (m,
4 H), 3.7 (m, 4 H) ppm.
2-(Piperidin-1-yl)benzoxazole (5c, Table 3, entry 6): GC–MS (EI, 70 eV): m/z
(%) = 216 (100), 187 (23), 161 (29), 148 (50).
2-(Pyrrolidin-1-yl)benzoxazole (5d, Table 3, entry 7): GC–MS (EI, 70 eV): m/z
(%) = 188 (100), 160 (58), 146 (15), 133 (92). 1H NMR (500 MHz, CDCl3, 25 °C):
d = 7.36 (d, J = 7.5 Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.00 (t,
J = 8 Hz, 1 H), 3.65 (t, J = 6 Hz, 4 H), 2.05 (t, J = 6 Hz, 4 H) ppm.
2-(4-Methylpiperazin-1-yl)benzoxazole (5e, Table 3, entry 8): GC–MS (EI, 70 eV):
m/z (%) = 217 (38), 160 (25), 147 (95), 70 (100).
1-(4-(Benzoxazol-2-yl)piperazin-1-yl)ethanone (5f, Table 3, entry 9): GC–MS (EI,
70 eV): m/z (%) = 245 (52), 160 (58), 147 (100), 43 (40). 1H NMR (500 MHz,
CDCl3, 25 °C): d = 7.37 (d, J = 7.5 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1 H), 7.2 (t,
J = 7.0 Hz, 1 H), 7.1 (t, J = 7.0 Hz, 1 H), 3.8–3.6 (m, 8 H), 2.16 (s, 3 H) ppm.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)benzoxazole (5g, Table 3, entry 10): GC–MS
(EI, 70 eV): m/z (%) = 250 (51), 134 (10), 117 (100), 104 (30).
4. (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013–3039; (b) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698–1712; (c) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174–238.
5. (a) Mori, A.; Sugie, A. Bull. Chem. Soc. Jpn. 2008, 81, 548–561; (b) Zificsak, C. A.;
Hlasta, D. J. Tetrahedron 2004, 60, 8991–9016; (c) Satoh, T.; Miura, M. Chem.
Lett. 2007, 36, 200–205; (d) Seregin, I. V.; Gevorgan, V. Chem. Soc. Rev. 2007, 36,
1173–1193.
6. (a) Yasuo, S.; Megumi, Y.; Satoshi, Y.; Tomoko, S.; Midori, I.; Tetsutaro, N.;
Kokichi, S.; Fukio, K. J. Med. Chem. 1998, 41, 3015–3021; (b) Yoshida, S.;
Shiokawa, S.; Kawano, K.-I.; Ito, T.; Murakami, H.; Suzuki, H.; Yasuo, S. J. Med.
Chem. 2005, 48, 7075–7079; (c) Gao, M.; Wang, M.; Hutchins, G. D.; Zheng, Q.-
H. Eur. J. Med. Chem. 2008, 43, 1570–1574; (d) Sato, Y.; Imai, M.; Amano, K.;
Iwamatsu, K.; Konno, F.; Kurata, Y.; Sakakibara, S.; Hachisu, M.; Izumi, M.;
Matsuki, N.; Saito, H. Biol. Pharm. Bull. 1997, 20, 752–755; (e) Verderame, M. J.
Med. Chem. 1972, 15, 693–694; (f) Liu, K. G.; Lo, J. R.; Comery, T. A.; Zhang, G.
M.; Zhang, J. Y.; Kowal, D. M.; Smith, D. L.; Di, L.; Kerns, E. H.; Schechter, L. E.;
Robichaud, A. J. Bioorg. Med. Chem. Lett. 2009, 19, 1115–1117.
7. Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282–2285. and
references therein.
8. (a) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132,
6900–6901; (b) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed.
2009, 48, 9127–9130; (c) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem.,
Int. Ed. 2010, 49, 9899–9903; (d) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu, X.-Q.
Chem. Commun. 2011, 47, 3652–3654; (e) Li, Y.; Xie, Y.; Zhang, R.; Jin, K.; Wang,
X. Duan., C J. Org. Chem. 2011, 76, 5444–5449.
9. (a) Joseph, J.; Kim, Y. J.; Chang, S. Chem. Eur. J. 2011, 17, 8294–8298; (b) Froehr,
T.; Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B. J. J. Org. Lett.
2011, 13, 3754–3757; (c) Lamani, M.; Prabhu, K. R. J. Org. Chem. 2011, 76, 7938–
7944; (d) Wagh, Y. S.; Sawant, D. N.; Bhanage, B. M. Tetrahedron Lett. 2012, 53,
3482–3485.
10. Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607–
1610.
N,N-Dibutylbenzoxazol-2-amine (5h, Table 3, entry 11): GC–MS (EI, 70 eV): m/z
(%) = 246 (30), 173 (21), 161 (46), 147 (100).
11. General experimental procedure:
N-Benzyl-N-methylbenzoxazol-2-amine (5i, Table 3, entry 12): GC–MS (EI,
70 eV): m/z (%) = 238 (66), 222 (41), 147 (46), 91 (100).
6-Methyl-2-morpholinobenzoxazole (5j, Table 3, entry 13): GC–MS (EI, 70 eV):
m/z (%) = 218 (97), 161 (100), 94 (12), 77 (13).
6-Methyl-2-(piperidin-1-yl)benzoxazole (5k, Table 3, entry 14): GC–MS (EI,
70 eV): m/z (%) = 216 (100), 187 (23), 161 (29), 147 (31).
In a 25 mL two necked round bottom flask, azole (1 mmol), amine (2.0 mmol),
Cu(acac)2 (52.6 mg, 20 mol %), and 5 mL xylene were added. The above mixture
was kept under reflux condition and then molecular oxygen was bubbled into
the reaction mixture till the completion of reaction. The progress of reaction
was monitored using gas chromatography. After completion of the reaction,
the reaction mixture was filtered through celite bed. The organic solvent was