One-pot synthesis of benzofused heteroaryl azoles via tandem C-heteroatom coupling/C-H activation of azoles

Article abstract of DOI:10.1039/c1cc10572h

The Cu(i) or Pd(ii)-catalyzed cross-couplings of gem-dihaloolefins with azoles via tandem C-heteroatom coupling/C-H activation for the preparation of benzofused heteroaryl azoles have been developed.

Full text of DOI:10.1039/c1cc10572h

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COMMUNICATION
One-pot synthesis of benzofused heteroaryl azoles via tandem
C-heteroatom coupling/C–H activation of azolesw
Xurong Qin, Xuefeng Cong, Dongbing Zhao, Jingsong You and Jingbo Lan*
Received 28th January 2011, Accepted 22nd March 2011
DOI: 10.1039/c1cc10572h
The Cu(I) or Pd(II)-catalyzed cross-couplings of gem-dihaloolefins
with azoles via tandem C-heteroatom coupling/C–H activation for
the preparation of benzofused heteroaryl azoles have been
developed.
route to diverse alkynyl azoles.10 Despite remarkable interest
in employing the gem-dihalovinyl substrates to achieve poly-
cyclic heteroaromatics via metal-catalyzed tandem amination
or Suzuki–Miyaura coupling/intramolecular C–H activation,11
to our knowledge the tandem processes via an intermolecular
C–H functionalization to form biheteroaryl units have not yet
been explored. Herein, we disclose an effective domino Cu(I)
or Pd(II)-catalyzed Ullmann-type C-heteroatom coupling of
gem-dihaloolefins/C–H activation of azoles to create various
benzofused heteroaryl azoles (Scheme 1). This sequential
strategy could offer a straightforward and highly efficient
alternative to access benzofuranyl, benzothiophenyl and indolyl
azoles, and avoid tedious separation and purification of inter-
mediate products.
Benzofuranyl, benzothiophenyl and indolyl azoles are a class
of privileged biheteroaryl structural motifs in bioactive natural
products, pharmaceuticals (e.g., anxiety inhibitor, and tumor
antagonist),1 and organic functional materials.2 The conven-
tional methods to forge these heteroaryl azoles mainly involve
intermolecular condensations of heteroaryl carboxylic acids
or aldehydes with o-aminophenols, benzene-o-diamines or
o-aminobenzenethiols.3 The transition metal-catalyzed coupling
reactions of azoles with heteroarenes also represents one of the
effective methodologies for the preparation of these biheteroaryl
units. However, such heteroaryl-heteroaryl bond-forming
examples are sporadic in both of traditional Ar–X/Ar–M
couplings4 and direct C–H bond functionalization.5 Despite
remarkable advances in these types of transformations, from
academic and practical standpoints, development of reliable
alternatives for the straightforward synthesis of these benzofused
heteroaryl azoles, especially starting from other readily available
sources, is still very attractive to synthetic and medicinal
chemists.
Inspired by our previous study on copper-catalyzed direct
arylation of heteroaromatic C–H bonds,12 we initially focused
on copper-catalytic systems due to economic attractiveness
and good functional tolerance. Our investigation started with
the coupling of 2-gem-dibromovinylphenol 1a and benzothiazole
2a in the presence of CuI and Phen (1,10-phenanthroline)
using K3PO4 as the base in 1,4-dioxane for 24 h at 120 1C. To
our delight, the biheteroaryl product 3a was obtained in 55%
yield (Table 1, entry 1). Subsequently, we examined several
bases (i.e., t-BuOK, Cs2CO3, K3PO4/NEt3, and t-BuOLi).
t-BuOLi proved to be the most efficient whereas the more
strongly basic t-BuOK only provided 28% yield of 3a (Table 1,
entries 2–5). After screening a series of ligands (e.g., Phen,
DMEDA (N,N0-dimethylethylenediamine), PPh3, and L-proline),
Phen turned out to be the best choice (Table 1, entries 5–9).
Among solvents investigated, 1,4-dioxane was clearly a more
efficient solvent (Table 1, entries 5, 10–11). Other sources of
the copper salt were inferior to CuI (Table 1, entries 5, 12–13).
In addition, prolonging reaction time, elevating reaction
temperature, and increasing CuI loading could significantly
improve yields (Table 1, entries 14–15). Thus, the best result
was obtained in 1,4-dioxane at 140 1C for 30 h using t-BuOLi
as the base in the presence of a catalyst system that was
generated in situ from CuI (20 mol%) and Phen (20 mol%).
The gem-dihalovinyl compounds as versatile partners have
attracted considerable interests in transition metal-catalyzed
cross-coupling chemistry owing to higher reactivity, and ready
availability from inexpensive aldehydes. Recently, a variety of
novel and elegant methods have been developed to allow the
Pd and/or Cu-catalyzed cross-couplings of gem-dihaloolefins
with various organometallic nucleophiles, nitrogen nucleo-
philes or dialkyl phosphites to form functionalized alkynes,6
dienes,7 heterocycles8 or carbocycles.9 Quite recently, Piguel
and co-workers described the first use of 1,1-dibromo-1-
alkenes in the intermolecular cross-coupling of azoles via the
direct functionalization of C–H bonds, providing an efficient
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University,
29 Wangjiang Road, Chengdu 610064, PR China.
E-mail: jingbolan@scu.edu.cn; Fax: (+86) 28-85412203
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, analytical data. See DOI: 10.1039/
c1cc10572h
Scheme 1 Tandem C-heteroatom coupling/C–H activation of azoles.
Chem. Commun., 2011, 47, 5611–5613 5611
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Table 1 Optimization of the coupling of 2-gem-dibromovinylphenol
with benzothiazolea
Table 2 Synthesis of 2-(benzofuran-2-yl)-azolesa,b
Entry Cu source Ligand
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Phen
Phen
Phen
Phen
Phen
—
PPh3
L-proline t-BuOLi
DMEDA t-BuOLi
K3PO4
t-BuOK
Cs2CO3
1,4-dioxane 55
1,4-dioxane 28
1,4-dioxane trace
K3PO4/NEt3 1,4-dioxane 16c
t-BuOLi
t-BuOLi
t-BuOLi
1,4-dioxane 64
1,4-dioxane 14
1,4-dioxane 25
1,4-dioxane 36
1,4-dioxane 29
9
10
11
12
13
14
15
Phen
Phen
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
toluene
DMF
20
25
CuBrꢀSMe2 Phen
1,4-dioxane 51
1,4-dioxane 45
1,4-dioxane 75d
1,4-dioxane 83e
CuBr
CuI
CuI
Phen
Phen
Phen
a
Reactions were carried out using copper(I) salt (10 mol%), ligand
(10 mol%), base (6 equiv), benzothiazole (0.25 mmol), and 2-gem-
b
dibromovinylphenol (0.5 mmol) for 24 h at 120 1C. Isolated yields.
c
d
e
K3PO4 (3 equiv), and NEt3 (3 equiv). 140 1C, 30 h. CuI (20
mol%), and ligand (20 mol%) for 30 h at 140 1C.
With the optimized conditions now in hand, we tested their
application to the one-pot synthesis of 2-(benzofuran-2-yl)-
azoles 3a–l. It was gratifying to find that a broad range of
azoles reacted smoothly with 2-gem-dibromovinylphenol in
good to excellent yields of desired products (Table 2). For
example, thiazoles (e.g., 4,5-dimethylthiazole, and benzothiazole)
gave the corresponding 2-(benzofuran-2-yl)-thiazoles in good
yields (Table 2, entries 3a–b). The catalytic system could be
also extended to an array of oxazoles (Table 2, entries 3c–f).
Notably, 2-(benzofuran-2-yl)-benzoxazole 3c, which is a
predominant chemical ingredient in sunscreens for the effective
protection of skin from sun radiation, was synthesized in 68%
yield.13 Worthy of note was that the reaction condition was
suitable for various imidazoles to furnish benzofuranyl imidazoles
(Table 2, entries 3g–k). For example, the coupling of 2-gem-
dibromovinylphenol with xanthines afforded 8-benzofuranyl
xanthines in good to excellent yields, which are important
biologically active alkaloids and highly potent antagonists at
human A2B adenosine receptors (Table 2, entries 3h–j).1e In
addition, 2-phenyl-1,3,4-oxadiazole was also reactive (Table 2,
entry 3l).
a
Reactions were carried out using CuI (20 mol%), Phen (20 mol%),
t-BuOLi (6 equiv), azole (0.25 mmol), and 2-gem-dibromovinylphenol
b
(0.5 mmol) for 30 h at 140 1C. Isolated yields.
(e.g., xanthine, 5-phenyloxazole, and 2-phenyl-1,3,4-oxadiazole)
smoothly gave the corresponding 2-(benzothiophen-2-yl)-
azoles under the optimized conditions (Table 3, 4i–k).
While the coupling of 2-gem-dibromovinylphenols and
2-gem-dibromovinylphenthiols with various azoles proceeded
well in the Cu(I)/Phen catalytic system, 2-gem-dibromovinyl-
benzenamine could not afford 2-(indole-2-yl)-azoles. However,
the catalyst system generated in situ from Pd(OAc)2/S-Phos/
CuI and t-BuOLi gave 2-(indol-2-yl)-benzothiazole 4l in 52%
yield in toluene at 120 1C for 24 h (Scheme 2).
In summary, we have developed the Cu(I) or Pd(II)-cata-
lyzed cross-coupling of gem-dihaloolefins with azoles via
tandem C-heteroatom coupling/C–H activation for the pre-
paration of benzofused heteroaryl azoles. Particularly note-
worthy is that our strategy is not only suitable for various
benzofused heterocycles (e.g., benzofurans, benzothiophenes,
and indole), but also a relatively wide range of azoles (e.g.,
thiazoles, oxazoles, imidazoles, and oxadiazoles). The reaction
conditions were also compatible with the presence of func-
tional groups (e.g., halides, nitro groups and methoxyl
groups), which may then be subject to further synthetic
transformations. Further studies aimed at elucidating the
mechanism of the reactions, and at extending this catalytic
method to other cross-coupling reactions are underway.
This work was supported by grants from the National NSF
of China (Nos 20872101, 20972102, 21025205, and 21021001),
To further expand the scope of our methodology, the
tandem cross-couplings of other 2-gem-dibromovinylphenol
derivatives were investigated as illustrated in Table 3. Overall,
we were pleased with the generality of our protocol. A
relatively wide arrange of 2-gem-dibromovinylphenols could
be efficiently converted into the corresponding benzofuranyl
azoles in synthetically useful yields (Table 3, 4a–h). On the
other hand, various azoles (i.e., thiazoles, oxazoles, and
imidazoles) were heteroarylated with 2-gem-dibromovinylphenols.
To our delight, this synthetic strategy was also applicable
for the synthesis of 2-(benzothiophen-2-yl)-azoles. Treatment
of 2-gem-dibromovinylphenthiol with various azoles
c
5612 Chem. Commun., 2011, 47, 5611–5613
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Table 3 Synthesis of 2-(benzofuran-2-yl)- or 2-(benzothiophen-2-yl)-
azolesa,b
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a
Reactions were carried out using CuI (20 mol%), Phen (20 mol%),
t-BuOLi (6 equiv), azole (0.25 mmol), and 2-gem-dibromovinylphenol
or 2-gem-dibromovinylphenthiol (0.5 mmol) for 30 h at 140 1C.
Isolated yields.
b
Scheme 2 Synthesis of 2-(indol-2-yl)-benzothiazole 4l.
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PCSIRT (No IRT0846), the National Basic Research Program
of China (973 Program, 2011CB8086600), and Doctoral Foun-
dation of Education Ministry of China (20090181110045). We
thank the Centre of Testing & Analysis, Sichuan University for
NMR measurements.
Notes and references
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5611–5613 5613