Copper and cobalt co-catalyzed aerobic oxidative cross-dehydrogenative coupling reaction of (benzo)azoles

Article abstract of DOI:10.1039/c9gc02464f

The dehydrogenative cross-coupling (CDC) reaction of diversely substituted azoles, synergistically catalyzed by copper and cobalt, is reported. This protocol represents the first example of the use of air as an oxidant to carry out this chemical reaction.

Full text of DOI:10.1039/c9gc02464f

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PAPER
Copper and Cobalt Co-Catalyzed Aerobic Oxidative Cross-
Dehydrogenative Coupling Reaction of (Benzo)Azoles
Yanrong Li,a Fen Qian,a Xia Ge,a Tao Liu,a Hitesh B. Jalani,c,d Hongjian Lua* and Guigen Lia,b*
Received 00th July 20xx,
Dehydrogenative cross-coupling (CDC) reaction of diversely substituted azoles, synergistically catalyzed by copper and cobalt
is reported. This protocol represents the first example of the use of air as an oxidant to carry out this chemical reaction. The
process provides a convenient and economical method for the construction of valuable unsymmetrical bis-heteroaryl
compounds, including bis-benzoazole compounds those were not described in previous catalytic CDC reactions.
www.rsc.org/
catalyst and copper/silver salts as oxidants.6 In 2012, You et al.
reported a challenging palladium-catalyzed CDC reaction
between two structurally similar azoles in presence of a copper
Introduction
Nitrogen-containing bis-heteroaryl compounds are important
structural architectures in a variety of molecules such as
commercially available pharmaceuticals, functional materials,
ligands and natural products.1 The transition-metal-catalyzed
cross-coupling reaction of two heteroaryl units with different
functional groups is one of the traditional approaches for the
synthesis of bis-heteroaryl compounds.2 Recently, transition
metal-catalyzed C−H heteroarylation has emerged as a direct
and effective method for the construction of bis-heteroaryl
compounds, in which heteroaryl compounds are directly
coupled with pre-functionalized aromatic heterocycles.3 The
cross-dehydrogenative coupling (CDC) reaction is an ideal
strategy for installation of C−C bonds, which circumvents pre-
functionalization of starting materials thereby greatly reducing
the reaction steps.4 However, the use of CDC reactions to
synthesize unsymmetrical bis-(benzo)azole compounds faces
mainly two challenges:4c,e,f 1) Electron rich (benzo)azoles are
prone to be oxidized, but oxidative conditions are generally
required in CDC reactions;4 and 2) The acidic C−H bonds in
(benzo)azoles are likely to be involved in self-coupling, which
makes it difficult to obtain unsymmetrical cross-coupled
products.5 Regardless of these challenges, the CDC strategy has
been used often, due to its high efficiency and the important
value of the unsymmetrical bis-(benzo)azoles1 (Scheme 1 A). In
2011, Ofial et al. used the CDC strategy for the first time in the
synthesis of bis-(benzo)azoles, wherein they coupled
benzthiazoles/benzimidazoles with azoles by using a palladium
salt as an oxidant.7 In same year, Wang et al. used a copper salt
as an oxidant to achieve coupling reactions of benzoazoles with
azoles.8 Zhang’s group achieved a CDC reaction of benzothiazole
with thiazole using catalytic amounts of a copper salt and a
stoichiometric quantity of silver carbonate.9 Transition-metal-
catalyzed CDC reactions of azoles suffer from a narrow scope of
substrates and are mostly limited to the coupling between
azoles7 and benzoazoles.6,8,9 As far as the coupling reactions of
two different benzoazoles are concerned, there is only one
example wherein the coupling reaction between 5-Br-
benzothiazole and 5-Br-benzoxazole has been reported to
date.10c However, the isolated yield of desired cross-coupling
product and the selectivity between self-coupling and cross-
coupling products were not mentioned. In addition, the
reported CDC reactions employed a stoichiometric amount of a
transition metal oxide as an oxidant, which is non-sustainable
from an environmental perspective. Consequently, it is
interesting to examine the cross coupling of azoles, especially
X
H
Y
Cat.; Oxidant
X
Y
+
N
N
CDC reaction
N
H
N
X, Y = N, O or S
A) Previous works
Cat.
Pd
Pd
--
oxidant
stoic. Cu/Ag6
stoic. Cu7
stoic. Cu8
X
X = NR, S; Y = NR, S, O
Y
N
N
azole-azole
benzoazole-azole
X = Y = S
Cu
stoic. Ag9
benzoazole-benzoazole (not reported)
a. Institute of Chemistry & BioMedical Sciences, Jiangsu Key Laboratory of Advanced
Organic Materials, School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing, (China) E-mail: hongjianlu@nju.edu.cn; guigenli@nju.edu.cn
b. Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX
79409-1061, USA
B) This work
X
Y
X = O, S; Y = O, S
Cat.
Co/Cu
oxidant
air
N
N
c.
Department for Management of Science and Technology Development, Ton Duc
including
Thang University, Ho Chi Minh City, Vietnam.
Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City,
benzoazole-benzoazole
d.
Vietnam.
Scheme 1. Metal-catalyzed CDC reactions of azoles
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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between two different benzoazoles, using a catalytic amount of (entries 17-20). Eventually, no desired product was obtained in
View Article Online
DOI: 10.1039/C9GC02464F
transition-metal salts in the presence of an environmental DMF or DMSO (entries 21-22).
friendly oxidant.
Table 1. Optimization of reaction conditions a
Air is a preferred oxidant in various transformations, due to
its abundance and environmental friendliness.11 However, the
combination of a single transition-metal as a catalyst and
oxygen as an oxidant in the coupling reactions of azoles tends
to produce self-coupled products.10 Recently, bimetallic
catalysis has emerged as a unique application in CDC
reactions,12,13 and not only controls the reactivity and selectivity
of two metalation processes associated with the catalyst cycles,
but also synergistically depresses the formation of undesired
self-coupling products, thereby improving the overall yields of
CDC reactions. In 2006, Li et al. reported the use of cobalt and
copper as co-catalysts of the CDC reaction of 1,3-dicarbonyl
compounds with allyl compounds.14 In 2015, Lei et al.
developed an interesting CDC reaction of aldehydes and
terminal alkynes, using zinc and indium as co-catalysts and
triethylamine as a base.15 In 2018, Zhang et al. reported cobalt
and manganese co-catalyzed aerobic oxidative cross-coupling
of compounds containing a directing group.16 Inspired by these
bimetallic catalyzed CDC reactions and our continuous research
on coupling reactions,17 we report here a cobalt and copper co-
catalyzed CDC reaction of (benzo)azoles using air as an oxidant,
18 leading to the efficient construction of various unsymmetrical
bis-(benzo)azole compounds including benzoazole-benzoazole
compounds.
catalyst (20 mol %)
additive (1.5 equiv)
S
H
O
S
O
+
N
N
air, solvent
130 oC, 18 h
N
1a
H
N
2a
3a
solvent
yield
Entry
1
catalyst
additive
Cu(OAc)2·H2O
Cu(OAc)2
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
1-F-2-CF3C6H4
–
–
–
–
–
48
47
2
3
4
5
6
7
8
9
10
11
12
13
14
CuCl2
CuBr2
AgNO3
AgOAc
none
none
10%
none
44
–
CoCl2
Co(acac)2
CoCO3
Co(NO3)2·6H2O
Co(ClO4)2·6H2O
CoBr2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
52
57
76
none
56
Co(acac)3
Co(OAc)2
48
54
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
15
1-F-2-CF3C6H4
28
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
Co(NO3)2·6H2O
Cu(OAc)2·H2Oc
16
17
18
19
20
21
22
CH3COONad
CH3COONad
CH3COONad
CH3COONad
CH3COONad
CH3COONad
CH3COONad
1-F-2-CF3C6H4
C6H5F
76
74
C6H5Cl
35
Results and discussion
Initially, benzothiazole (1a) and benzoxazole (2a) were used
as the model substrates in the solvent 1-fluoro-2-
(trifluoromethyl)benzene, and several metal oxides were
screened (Table 1, entries 1-6). Using 1.5 equivalents of
Cu(OAc)2•H2O or Cu(OAc)2 as the additive, the desired product
2-(benzothiazol-2-yl)-benzooxazole (3a) was obtained with 48%
and 47% yield, respectively (entries 1 and 2). No product was
obtained when CuCl2, CuBr2 or AgOAc were used, and only 10%
yield of 3a was obtained with AgNO3 (entries 3-6), indicating
that both copper and acetate ion support the formation of 3a.
Based on our cobalt-catalyzed C−H bond functionalization
studies reported previously,17 cobalt catalysts employing 1.5
equivalents of Cu(OAc)2•H2O as the oxidant were screened
(entries 7-14), and it was found the yield of 3a could be
increased up to 76% by using Co(NO3)2•6H2O as a catalyst.
Reduction of the amount of Cu(OAc)2•H2O to 20 mol % led to a
28% yield of 3a (entry 15). Considering the important role of
acetate ion in this reaction, we increased the level of acetate
ion by adding sodium acetate. It was found that addition of 1.0
equivalent of sodium acetate greatly enhanced the CDC
reaction, producing 3a in a yield of 76% in which Cu(OAc)2•H2O
and Co(NO3)2•6H2O was used as co-catalysts and air worked as
an oxidant (entry 16). Different solvents were then examined.
Fluorobenzene has also proved to be one of good choice. While
solvent such as chlorobenzene, bromobenzene and xylene
could provide desired product 3a in moderate to low yields
C6H5Br
xylene
DMF
39
48
none
none
DMSO
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (0.04 mmol), 1-fluoro-
2-(trifluoromethyl)benzene (0.8 mL), 130 oC, air, 18 h. Crude 1H NMR yields of
desired product 3a determined by using dibromomethane as an internal standard.
c Cu(OAc)2·H2O (20 mol %). d CH3COONa (1.0 equiv.).
b
With the optimum reaction conditions,
a range of
benzothiazole and benzoxazole substrates were screened
(Table 2). It was found that benzothiazole reacted not only with
benzoxazoles substituted with electron-rich groups (3b, 3c, 3d,
3g), but also with electron-withdrawing groups (3e, 3f),
affording the corresponding CDC products in good yields.
Benzoxazoles reacted with benzothiazoles substituted with an
electron-donating group (3i) or an electron-withdrawing group
(3h) to give the desired products with good yields. In addition,
benzothiazoles containing different substituents were also
found to undergo CDC reactions efficiently with benzoxazoles
with different substituents, providing bis-benzoazole
compounds with different functional groups (3j-3o). This
provides the possibility of further subsequent modification of
the bis-heterocyclic products. 4-Cl-Benzoxazole and 7-Cl-
2 | J. Name., 2012, 00, 1-3
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Table 2. Synthesis of benzoxazole-benzothiazole products a,b
bibenzoxazole (5a) was decreased to 12% (entry 2)V.i1e9wWArthicleenOntlhinee
reaction was attempted under an inert gas such as argon, the
DOI: 10.1039/C9GC02464F
R1
R1
H
S
O
standard
conditions
Table 3. Scope of other substrates a,b
R2
S
N
+
N
R2
N
N
O
H
R1
1
2
3
R1
standard
conditions
H
Y
X
R2
X
+
Y
S
S
N
N
R2
S
S
N
H
O
O
N
N
N
O
O
X = O, S
N
N
2
1
3
N
N
N
N
Me
benzoxazole-benzoxazole
benzothiazole-benzothiazole
Me
OMe
Me
O
c
O
3a,
3b,
3c
, 75%
3d,
73% (60% )
71%
78%
S
Me
O
N
O
N
O
S
N
O
N
N
N
N
S
S
N
OMe
S
Cl
Me
S
O
N
O
N
O
N
tBu
N
N
O
t-Bu
N
N
3r,
3s,
71%
69%
3p,
3q,
66%
71%
O
N
benzoxazole-oxazole
benzoxazole-thiazole
Ph
t-Bu
Cl
3e,
3f,
3g,
3h,
62%
69%
74%
72%
O
Me
t-Bu
O
MeO
O
S
MeO
MeO
N
O
O
O
Me
Cl
N
N
N
S
Ph
Ph
Ph
N
S
N
N
O
N
S
S
N
Me
3w,
64%
O
N
O
O
3t,
3u,
3v,
60%
53%
62%
N
N
N
N
N
N
benzothiazole-thiazole
Me
t-Bu
MeO
OMe
3i,
3j,
3k,
3l,
51%
67%
72%
63%
Me
t-Bu
S
O
N
O
S
S
S
S
N
N
S
Me
Me
Me
MeO
MeO
MeO
N
Me
N
N
N
N
Me
Me
Me
S
S
S
Me
74%
O
3x,
3y,
3z,
68%
3a',
O
65%
67%
O
N
N
N
N
N
N
benzothiazole-oxazole
MeO
Me
Cl
t-Bu
Me
S
S
Me
3m,
3n,
3o,
62%
75%
73%
Me
S
O
N
O
N
Ph
O
N
Ph
a
N
Standard conditions: 1 (0.2 mmol), 2 (0.3 mmol), Co(NO3)2·6H2O (0.04 mmol),
Ph
N
N
Cu(OAc)2·H2O
(0.04
mmol),
NaOAc
(0.2
mmol),
1-fluoro-2-
3b',
51%
3c',
3d',
54%
61%
(trifluoromethyl)benzene (0.8 mL), 130 oC, air, 18 h. b Isolated yield of product 3,
a Standard conditions, same as note in Table 2. b Isolated yield of product 3, small
c
small amount of homo-coupling products were also observed. With 1.0 mmol
scale.
amount of homo-coupling products were also observed.
benzoxazole could not react with benzothiazole (1a) under yields of both cross-coupling and self-coupling products were
standard conditions, possibly due to the influence of steric reduced, indicating that oxygen present in the air participated
hindrance.
in the reaction (entry 3). To further understand the influence of
The scope of the other types of heterocyclic substrates was Cu(OAc)2•H2O, Co(NO3)2•6H2O and NaOAc in this reaction,
explored with the optimal reaction conditions (Table 3). The control experiments were conducted (entries 4-7). It was found
substrates underwent coupling reactions with similar that no product 3a was formed in the absence of Cu(OAc)2•H2O
substrates. For example, benzoxazole coupled with 5-tBu- (entry 4), and the selectivity to the cross-coupling product 3a
benzoxazole (3p), 5-Me-benzoxazole reacted with 5-tBu- was reduced in the absence of Co(NO3)2•6H2O and/or NaOAc
benzoxazole (3q) or 6-Me-benzoxazole (3r), and benzothiazole (entries 5-7).10c When the reaction was performed with a
reacted with 6-MeO-benzothiazole (3s). In addition, the stoichiometric amount of Cu(OAc)2 but with no Co(NO3)2•6H2O,
previously reported5-8 cross-coupling reactions of benzoazoles 3a was produced in 42% yield with good selectivity between
with azoles were also examined and the desired products were cross-coupling and self-coupling reactions (entry 8). In order to
isolated in moderate to good yields. For example, benzoxazoles assess the selectivity of the cross-coupling reaction more
could be combined with oxazoles or thiazoles (3t-3y), clearly, the reaction was conducted with a one-to-one ratio of
benzothiazoles could react with oxazoles and thiazoles (3z, 3a', substrates 1a and 2a, and it was found in this case that the yield
3b') and finally, thiazoles and oxazoles could couple with one of the product (3a) was slightly reduced to 54%, but the
another (3c', 3d').
selectivity was acceptable. The yields of self-coupling products
Several control experiments were conducted in an attempt to were 8% (4a) and 16% (5a), respectively (entry 9). Additionally,
understand the mechanism of this CDC reaction (Table 4). When the solvent screening experiments showed good selectivity in 1-
the reaction was performed in an oxygen atmosphere, the yield fluoro-2-(trifluoromethyl)benzene and fluorobenzene (entries
of the cross-coupling reaction was reduced to 56%, the yield of 1, 10-15). These control experiments demonstrate that a
self-coupling product 2,2'-bibenzothiazole (4a) was increased to catalytic amount of Cu(OAc)2•H2O is indispensable for the
22% and the yield of the self-coupling product 2,2'- formation of the cross-coupling product, and a catalytic amount
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of Co(NO3)2•6H2O and the solvent of fluoro-2-
(trifluoromethyl)benzene or fluorobenzene are good for the
View Article Online
DOI: 10.1039/C9GC02464F
A) Self-coupling reactions
S
O
standard
standard
conditions
Table 4. Control experimentsa
conditions
S
O
1a
2a
N
N
N
N
S
S
O
4a, 10%c
5a, 38%c
standard
conditions
1a
+
O
S
O
+
+
N
N
N
Radical trapping experiment
B)
2a
N
N
N
TEMPO
-
3a
yield of
76%
S
(
equiv)
1.5
standard conditions
3a
4a
5a
O
N
N
1a
2a
+
1.0 equiv
2.0 equiv
3.0 equiv
68%
64%
65%
TEMPO
entry change from standard conditions
3a
76
56
8
4a
8
5a
34
12
6
3a
1
2
3
4
5
6
7
8
–
Intermolecular competition experiments
C)
oxygen instead of air
argon instead of air
no Cu(OAc)2•H2O
no Co(NO3)2•6H2O
no Co(NO3)2•6H2O, no NaOAc
no NaOAc
22
10
0
standard
conditions
O
O
S
+
N
Cl
N
N
Me
0
0
1a
2b
0.2 mmol
2e
0.4 mmol
0.2 mmol
34
26
28
42
trace
trace
trace
12
39
22
10
5
Me
O
S
S
N
O
O
O
N
N
Cu(OAc)2•H2O (1.5 equiv),
no Co(NO3)2•6H2O
+
N
N
N
b
9
–
54
74
35
39
48
0
8
10
12
10
18
0
16
33
34
29
32
0
Me
Cl
Cl
3b, 31%
3e, 15%
trace
10
11
12
13
14
15
C6H5F
C6H5Cl
C6H5Br
xylene
DMF
Scheme 2. Mechanism studies
O2
CoIII
Cu(OAc)
X
CoIIX
2a
HOAc
O
Cu(OAc)2
DMSO
0
0
0
N
CuOAc
NaOAc
Cu(OAc)2
Crude 1H NMR yields of products 3a, 4a and 5a determined by using
dibromomethane as an internal standard. 2a (1.0 equiv).
a
A
3a
b
1a
O
N
CuOAc
OAc
Cu
O
S
selectivity of the cross-coupling product, and the acetate ion
increases the efficiency of this cross-coupling reaction.
N
B
Cu(OAc)2
N
C
In order to probe the selectivity of this reaction, several
Co/Cu co-catalyzed oxidative coupling reactions were
performed (Scheme 2). When one of the starting compounds,
either 1a or 2a was allowed to react under standard conditions,
it was found that self-coupling products were obtained with
yields of only 10% (4a) and 38% (5a), respectively (Scheme 2A).
It was clear that the reaction conditions used tend to inhibit the
self-coupling reaction and preferentially generate a cross-
coupling product. When the reaction was performed in the
Scheme 3. Proposed catalytic cycle
presence of 1.0, 2.0 or 3.0 equiv. of (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO), free radical
a
scavenger, the yields of 3a remained mainly unaffected
(Scheme 2B), suggesting that a radical mechanism is not
involved in the reaction. Intermolecular experiments showed
that benzoxazole substituted with an electron-donating group
takes preference in the reaction and very little cross-coupling of
benzoxazoles 2b and 2e was observed (Scheme 2C).
Based on our experimental results and previous related
reports,4,14 a possible reaction mechanism is proposed and is
shown in Scheme 3. Since that it is known that the reaction can
be initiated by a concerted metalation-deprotonation process
of the relatively more acidic heteroarene’s C−H bond,8,20 the
copper is prone to react with benzoxazole first to form the
intermediate (A) with the assistance of sodium acetate. Then, A
reacts with Cu(OAc)2 to produce a Cu(III) intermediate (B).21 The
second concerted metalation-deprotonation process of
benzothiazole’s C−H bond promoted by B results in the key
heterocoupling intermediate species C, which might be rate-
determining procedure in the reaction and prone to carry
out.22,23 Subsequently, C undergoes reductive elimination to
form the cross-coupling product (3a) and CuOAc. Finally, the
CuOAc is oxidized by the cobalt (III) species which is produced
by the air oxidation of cobalt (II),16 and the addition of sodium
4 | J. Name., 2012, 00, 1-3
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1113; (j) M. E. Cinar and T. Ozturk, Chem. Rev. 2015, 115, 3036;
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acetate may make up for the reduction of acetate ion,
regenerating Cu(OAc)2 and continuing the next cycle.
2
3
Conclusions
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In summary, we have developed
a CDC reaction of
(benzo)azoles with a co-catalytic system of Co(NO3)2•6H2O and
Cu(OAc)2•H2O. With the assistance of CH3COONa, the reaction
uses air as an oxidant and produces cross-coupling products
with good selectivity and moderate to good isolated yields. This
co-catalytic system avoids the use of stoichiometric amounts of
metal oxidants, thereby providing an economical and
environmentally acceptable method for the construction of
important unsymmetrical bis-heteroaryl compounds, including
bis-benzoazoles which were not observed in previously
reported catalytic CDC reactions. Further work on this
newlydeveloped CDC, possibly providing access to other
interesting heterocycles, is currently underway and will be
reported in due course.
Experimental
A
35 mL oven-dried pressure tube was charged with
4
benzothiazole (1a) (27.0 mg, 0.2 mmol), benzoxazole (2a) (35.8
mg, 0.3 mmol), Cu(OAc)2·H2O (8 mg, 0.04 mmol), Co(NO3)2·6H2O
(11.7 mg, 0.04 mmol), CH3COONa (16.4 mg, 0.2 mmol), and 1-
fluoro-2-(trifluoromethyl)benzene (0.8 mL). The tube was
sealed and stirred vigorously at 130 ˚C for 18 h, then, cooled to
room temperature, diluted with ethyl acetate, filtered through
a celite pad and concentrated under reduced pressure. The
residue was purified by silica gel chromatography
(dichloromethane/hexane (v/v): 10/1 to 1/1) to give the desired
benzothiazol-2-yl)benzoxazole (3a) (45 mg, 73% yield).
5
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6
7
8
9
Acknowledgements
We would like to acknowledge the financial support from the
National Natural Science Foundation of China (No. 21672100,
21871131) and Robert A. Welch Foundation (D-1361, USA).
10 (a) Y. Li, J. Jin, W. Qian and W. Bao, Org. Biomol. Chem. 2010,
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There are no conflicts to declare.
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Green Chemistry
View Article Online
X
H
DOI: 10.1039/C9GC02464F
N
Cat. Co/Cu
Air
X
Y
N
+
Y
N
H
N
X , Y = O or S
CDC reaction
30 examples
Dehydrogenative cross-coupling (CDC) reaction of diversely substituted azoles was
realized by copper and cobalt co-catalysis under air conditions.