Highly regioselective palladium-catalyzed direct alkenylation of thiazolo[3,2-b]-1,2,4-triazoles via CH activation

Article abstract of DOI:10.1016/j.tetlet.2014.04.095

An efficient and regioselective palladium-catalyzed oxidative cross-coupling reaction between thiazolo[3,2-b]-1,2,4-triazoles and alkenes has been developed. This protocol provides easy access to a variety of functionalized thiazolo[3,2-b]-1,2,4-triazole derivatives.

Full text of DOI:10.1016/j.tetlet.2014.04.095

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly regioselective palladium-catalyzed direct alkenylation
of thiazolo[3,2-b]-1,2,4-triazoles via CAH activation
⇑
Wenjie Liu, Shaohua Wang , Haiying Zhan, Juan Lin, Peiling He, Yi Jiang
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and regioselective palladium-catalyzed oxidative cross-coupling reaction between thiazol-
o[3,2-b]-1,2,4-triazoles and alkenes has been developed. This protocol provides easy access to a variety
of functionalized thiazolo[3,2-b]-1,2,4-triazole derivatives.
Received 8 February 2014
Revised 21 April 2014
Accepted 28 April 2014
Available online xxxx
Ó 2014 Published by Elsevier Ltd.
Keywords:
Dehydrogenative cross-coupling
Thiazolo[3,2-b]-1,2,4-triazole
Alkenylation
Regioselectivity
CAH activation
Over the past few decades, transition-metal-catalyzed alkenyla-
tion reaction has become one of the most powerful tools in modern
organic chemistry.1 Many successful strategies, such as Mizoroki–
Heck,2 Suzuki–Miyaura,3 and Kumada4 cross-coupling reactions
have been developed with a variety of metal catalysts. These pro-
cesses require a preactivated coupling partner (C-X or C-M) that
is often not commercially available or is relatively expensive,
resulting in longer synthetic sequences and environmental
problems.
More recently, dehydrogenative cross-coupling reactions of are-
nes or heteroarenes with alkenes via CAH bond cleavage, also
called ‘Fujiwara–Moritani reaction’ have become an exceedingly
valuable process.1b,c,5 Because this transformation is more atom-
economical and minimizes the costs of prefunctionalization. The
Fujiwara group reported the first examples of alkenylation of elec-
tron-rich aromatics with alkenes in the presence of a palladium
catalyst.5a Up to date, lots of efforts have been devoted to the direct
alkenylation of various heteroaromatic scaffolds through oxidative
Heck reaction to build complex frameworks.6 However, the regio-
selective CAH functionalization is an important challenge in this
area.
alkyl thiazolo[3,2-b]-1,2,4-triazole moiety have been reported to
possess biological activities.12 Thus, developing efficient ways to
construct novel thiazolo[3,2-b]-1,2,4-triazole derivatives is desir-
able. Direct CAH functionlization of thiazolo[3,2-b]-1,2,4-triazole
to construct CAC bonds has been achieved via Pd and Cu catalysis
(Table 1).13
Inspired by the successful results in our recent research on the
direct arylation of thiazolo[3,2-b]-1,2,4-triazoles,13c,d we herein
report the first example of direct palladium-catalyzed alkenylation
of thiazolo[3,2-b]-1,2,4-triazoles with alkenes via twofold CAH
functionalization.
As an initial attempt, 6-methylthiazolo[3,2-b]-1,2,4-triazole 1a
with n-butyl acrylate 2a in the presence of 10 mol % Pd(OAc)2
and 2.0 equiv of benzoquinone (BQ) was firstly attempted in diox-
ane at 110 °C for 12 h, the desired coupling product 3a was
obtained in 23% yield (entry 1). It is particularly noteworthy that
the reaction gave the alkenylation product with complete C-5 reg-
ioselectivity and E stereoselectivity. Various oxidants such as
K2S2O8, Cu(OAc)2, Ag2CO3, AgOAc, and Ag2O were used, Cu(OAc)2
proved to be the most effective oxidant and the yield of product
3a was promoted to 72% (entries 2–6). When pure oxygen or no
oxidant was tested, the yield of product 3a was 17% or 6%, respec-
tively (entries 7 and 8). Considering the synergistic effect of metal-
oxidant with pure oxygen on improving the CAH activation reaction
efficiency,14 the yield remarkably increased to 85% after choosing
Cu(OAc)2/O2 as the co-oxidant (entry 9). After careful solvent
screening, other solvents such as DMSO, DMF, AcOH, and CH3CN
gave lower yields than dioxane (entries 10–13). Reducing the
Thiazolo[3,2-b]-1,2,4-triazole is a common motif found in many
natural products, drugs, and synthetic molecules,7 including anti-
inflammatory,8 antimicrobial,9 anticancer,10 and antibacterial
activities.11 Some of these compounds featured with 5-vinyl or 5-
⇑
Corresponding author. Tel./fax: +86 76088207939.
E-mail address: wangshaohua108@163.com (S. Wang).
http://dx.doi.org/10.1016/j.tetlet.2014.04.095
0040-4039/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Liu, W.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.095

2
W. Liu et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
Ph
Cl
Optimization coupling reaction of 6-methyl-thiazolo[3,2-b]-1,2,4-triazole 1a with n-
N
N
N
butyl acrylate 2a under various conditionsa
COOEt
S
CH3
CH3
3k, 79%
N
N
N
N
N
N
N
Cat. Pd
Oxidant
COOnBu
N
COOnBu
H
H
COOnBu
H
+
S
S
N
S
3l, 83%
1a
2a
3a
Cl
Entry
Cat
Oxidant
BQ
K2S2O8
Cu(OAc)2
Ag2CO3
AgOAc
Ag2O
O2
—
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMSO
DMF
AcOH
CH3CN
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
23
11
72
41
28
19
17
6
85
53
72
76
N
N
N
COOtBu
S
3m, 85%
a
All reactions were performed with
1
(0.5 mmol),
2
(1.0 mmol), Pd(OAc)2
(10 mol %), Cu(OAc)2 (2 equiv), O2 (gas bag), in 2 mL of dioxane at 110 °C for 12 h.
The yields are of the isolated products. The E diastereomer was exclusively formed.
9
10
11
12
13
14
15
16
17
18
amount of Pd(OAc)2 or employing other palladium catalysts (PdCl2
or Pd(OH)2) also decreased the yields (entries 14–16). Moreover,
the yield of product 3a decreased by using a catalytic amount or
the same stoichiometric amount of Cu(OAc)2 (entries 17 and 18).
Having established the optimal conditions for the oxidative
Heck reaction of 6-methylthiazolo[3,2-b]-1,2,4-triazole 1a with
n-butyl acrylate 2a, we next explored the regioselective alkenyla-
tion of 6-substituted thiazolo[3,2-b]-1,2,4-triazoles and results
are exhibited in Table 2. To our delight, the sole C-5 alkenylation
products were observed. Activated olefins such as n-butyl, t-butyl,
or ethyl acrylate worked well to provide products in good yields
(Table 2, products 3a–c, 3i–m). The t-butyl group was more
favored than n-butyl or ethyl group in this reaction. Other alkenes
such as styrene and p-methylstyrene also provided the desired
products (3d, 3e) in moderate yields. As expected, acrylamide
and methylvinylketone were also good alkenylating partners and
gave the corresponding products 3f and 3g. A low yield was pro-
duced with acrylic acid (3h, 33%). Notably, thiazolo[3,2-b]-1,2,4-
triazoles bearing large R1 groups (phenyl, p-chlorophenyl) were
not shown a steric effect on yields.
35
73c
43
Pd(OH)2
Pd(OAc)2
Pd(OAc)2
56
32d(37)e
68f
a
Reaction conditions: 6-methylthiazolo[3,2-b]-1,2,4-triazole 1a (0.5 mmol), n-
butyl acrylate 2a (1.0 mmol), catalyst (10 mol %), oxidant (2 equiv), O2 (gas bag) in
2 mL of solvent at 110 °C for 12 h.
b
GC yield.
Pd(OAc)2 (5 mol %).
Cu(OAc)2 (0.1 equiv), 12 h.
Cu(OAc)2 (0.1 equiv), 24 h.
c
d
e
f
Cu(OAc)2 (1 equiv), 12 h.
Table 2
A regioselective alkenylation of thiazolo[3,2-b]-1,2,4-triazolesa
R1
Pd(OAc)2
Cu(OAc)2/O2
R1
N
N
N
N
N
N
R2
+
R2
dioxane, 110°C
S
S
The thiazolo[3,2-b]-1,2,4-triazoles bearing different groups at 2
and 6-positions were also investigated and results are shown in
Table 3. As can be seen from Table 3, the coupling reactions of
thiazolo[3,2-b]-1,2,4-triazoles (1d–h) with various alkenes
smoothly generated the corresponding products (4a–q) in moder-
ate to good yields. The p-fluorostyrene with electron-withdrawing
group led to a slightly low yield (product 4e). The substituted
groups at 2-position of thiazolo[3,2-b]-1,2,4-triazoles have no
obvious influence on this reaction system.
1a-c
3
2
CH3
CH3
N
N
N
N
N
N
N
N
N
N
COOnBu
COOEt
COOtBu
S
S
3a, 82%
3b, 85%
CH3
CH3
N
N
N
N
N
N
N
N
S
S
Thiazolo[3,2-b]-1,2,4-triazole contains both a
p-excessive thia-
3c, 77%
3d, 78%
CH3
zole ring and a -deficient triazole ring. The C-5 position is more
p
CH3
nucleophilic than the C-2 position in the thiazolo[3,2-b]-1,2,4-tria-
zole ring, which is most likely first attacked by the Pd(II) species.
On the basis of the exclusive C-5 regioselectivity and the literatures
N
N
N
N
CONHC(CH3)3
COOH
CH3
S
S
p
-excessive aromatics,1b,6f–h,15
3f, 83%
3e, 75%
CH3
about direct alkenylation of some
CH3
an electrophilic palladation pathway was proposed in Figure 1. Ini-
tially, electronic attack of Pd(II) on 6-methylthiazolo[3,2-b]-1,2,4-
triazole 1a in the C-5 position forms intermediate I. Active inter-
mediate I then inserts into the alkene to form intermediate II,
which rapidly decomposes through b-elimination to afford the tar-
get products. Finally, Pd(0) is recycled by the cooperation of the
oxidant.
In summary, we have developed an efficient and highly atom-
economical method for the palladium-catalyzed dehydrogenative
coupling reaction of thiazolo[3,2-b]-1,2,4-triazoles and alkenes.
The protocol provides the desired products in moderate to good
yields and with regio- and stereoselectivities. Further studies to
N
N
N
N
COCH3
S
S
3g, 71%
3h, 33%
Ph
Ph
N
N
N
N
COOnBu
COOtBu
S
S
3j, 87%
3i, 83%
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W. Liu et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 3
The scope of thiazolo[3,2-b]-1,2,4-triazoles without regioselectivitya
R1
Pd(OAc)2
Cu(OAc)2/O2
R1
N
N
N
N
N
R3
R2
+
R2
R3
dioxane, 110°C
S
S
N
1d-h
2
4
CH3
CH3
N
N
N
N
N
N
N
N
N
Ph
Ph
COOnBu
COOEt
Ph
Ph
COOtBu
S
S
4a, 86%
4b, 87%
CH3
CH3
N
N
N
N
S
S
4c, 80%
4d, 77%
CH3
CH3
N
N
N
N
H3C
H3C
COOnBu
Ph
F
S
S
N
4e, 71%
4f, 82%
CH3
CH3
N
N
N
N
N
H3C
COOtBu
COOEt
CH3
S
S
N
4g, 84%
4h, 77%
CH3
N
N
N
N
Cl
Cl
COOnBu
COOEt
Cl
COOtBu
S
S
N
N
4i, 83%
4j, 86%
CH3
CH3
N
N
N
N
N
H3C
COOnBu
COOEt
S
N
S
4l, 87%
4k, 79%
CH3
CH3
N
N
N
N
H3C
COOtBu
H3C
Ph
S
N
S
N
4m, 88%
Ph
4n, 82%
Ph
N
N
N
N
N
Ph
Ph
COOnBu
COOtBu
S
S
N
N
4o, 88%
Ph
4p, 90%
N
N
COOEt
S
4q, 82%
aAll reactions were performed with 1 (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2 (2 equiv), O2 (gas bag), in 2 mL of dioxane at 110 °C for 12 h. The yields are of
the isolated products. The E diastereomer was exclusively formed.
CH3
N
N
expand the substrate scope and their potential biological activities
S
N
are currently underway.
1a
Pd(OAc)2
oxidant
HOAc
Acknowledgments
The work was financially supported by the Foundation for
Natural Science Foundation of Guangdong Province (S20130400
12962), Distinguished Young Talents in Higher Education of
Guangdong (2012LYM_0086), Department of Education of
Guangdong (2013KJCX0111), and the National Natural Science
Foundation of China (21302023, 21301035).
CH3
N
N
PdOAc
Pd(0)
S
N
I
CH3
CH3
PdOAc
R
R
N
N
N
N
N
S
II
N
2
Supplementary data
R
S
Supplementary data (1H and 13C NMR spectra of compunds 3a–
m and 4a–q) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2014.04.095.
3a
Figure 1. A plausible mechanism for the reaction.
Please cite this article in press as: Liu, W.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.095

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W. Liu et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Silva, J.; Thérien, M.; Vvanstaden, C.; Wong, E.; Xu, L.; Prasit, P. Bioorg. Med.
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Please cite this article in press as: Liu, W.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.095