Palladium-catalyzed c-2 selective olefination of thiazoles

Article abstract of DOI:10.1021/ol500542j

A highly efficient protocol for C2 selective alkenylation of electron-deficient thiazoles is developed. High C2 position selectivity for alkenylation products is achieved at a neutral environment, and a possible pathway of oxidative alkenylation is discussed. This methodology provides a simple way to construct a 2-alkenyl-thiazole moiety.

Full text of DOI:10.1021/ol500542j

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C‑2 Selective Olefination of Thiazoles
Wei Liu, Xin Yu, and Chunxiang Kuang*
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, P. R. China and Key Laboratory of Yangtze River
Water Environment, Ministry of Education, Siping Road 1239, Shanghai 200092, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient protocol for C2 selective
alkenylation of electron-deficient thiazoles is developed. High
C2 position selectivity for alkenylation products is achieved at a
neutral environment, and a possible pathway of oxidative
alkenylation is discussed. This methodology provides a simple
way to construct a 2-alkenyl-thiazole moiety.
ince the discovery of the transition-metal-catalyzed
Soxidative olefination of benzene by Fujiwara, significant
progress has been made to improve the efficiency and
practicality of the oxidative Heck reaction.1 The scope of
direct alkenylation partners has broadened to include various
directing groups,2 electron-rich (hetero)arenes,3 and even some
examples for the site-selective C−H olefination of electron-
deficient (hetero)arenes.4
A thiazole-containing structural motif is frequently featured
at the core of pharmaceuticals and organic materials.5
Considering their importance, great successes have been
accomplished regarding transition-metal-catalyzed direct aryla-
tion6 and alkylation7 of thiazoles, including oxidative C−H/C−
H coupling reactions. To our knowledge, the most direct
olefination of thiazoles still relies on the use of alkenyl
bromides as coupling partners,8 but commercially available
alkenyl halide are still limited. However, in sharp contrast to
those extensive studies, the C−H/C−H oxidative olefination of
thiazoles has rarely been reported because of their tendency to
undergo homocoupling toward oxidative environments. More-
over, direct olefination of thiazoles remains a daunting
challenge in the selectivity inversion between C2 and C5
positions.9
Based on our ongoing interest in exploring C−C bond
formations through cross-dehydrogenative coupling reac-
tions,2b,10 we report in this paper an efficient and highly
regioselective protocol for oxidative olefination at the C2
position of electron-deficient thiazoles. This simple and novel
method provides access to 2-alkenylthiazole derivatives that are
closely related to a variety of biologically active natural
products, like artemisinin, and drug molecules such as
epothilone C (Figure 1).
Figure 1. Representatives of thiazole-containing compounds.
Ag2SO4), the corresponding products were obtained with low
yields. AgNO3 was found to be the optimal oxidant for this
reaction.
Encouraged by this preliminary result, a variety of solvents
were screened (entries 5 to 8); as a result, DMSO was selected
as the most effective solvent compared to others such as 1,4-
dioxane, DMF, and toluene. An improved yield (89%) was
obtained by lowering the reaction temperature from 125 to 100
°C (entries 9 to 11). In addition, the yield of this reaction could
be slightly diminished when no 1,10-phenanthroline was used.
Thus, the optimal reaction conditions were obtained when 5
mol % of Pd(OAc)2 was used in combination with 1,10-
phenanthroline (30 mol %) and AgNO3 (1.5 equiv) at 100 °C
in DMSO (entry 9). Furthermore, this Heck reaction
proceeded with complete stereoselectivity and generated (E)-
3a exclusively.
We initially employed reported conditions4c,10 for the
oxidative Heck reaction of 4,5-dimethylthiazole (1a) and
methyl acrylate (2a), but no desired product was observed
(Table 1, entry 1). As shown in Table 1, a few types of simple
silver and copper salts were tested (entries 1 to 5), where all
incomplete ionization silver and copper salts (Ag2CO3,
Cu(OAc)2, and AgOAc) failed to obtain any desired product;
in the case of complete ionization of silver salts (AgNO3 and
With the optimized conditions identified (Table 1, entry 9),
we further examined the scope of other thiazole derivatives and
alkenes for C-2 alkenylation reactions (Scheme 1). We first
Received: February 19, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Letter
a
olefination methodology in high yields (Scheme 1, compounds
3g−3r) without any observable homocoupling products.
Interestingly, 1-octene was applied to the standard
conditions, affording the branched product 3s in moderate
yield (58%) (Scheme 2). Notably, no desired product was
observed under the above conditions when vinyl acetate and
allyl acetate were used as substrates.
Table 1. Optimization of Typical Reaction Conditions
c
entry
oxidant
solvent
t (°C)
yield (%)
1
Ag2CO3
AgOAc
Cu(OAc)2
Ag2SO4
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
125
125
125
125
125
125
125
125
100
75
trace
trace
trace
18
Scheme 2. Reaction of 3a with 1-Octene
2
3
4
5
31
6
65
7
DMSO
toluene
DMSO
DMSO
DMSO
DMSO
81
8
48
9
89
The C2 position of the thiazole moiety is known to possess
lower electron density than the C5 position, whereas it has
higher electron density than the C4 position.6d However, we
found that the only C2 alkenylation products were obtained in
high yields when 4-methylthiazole as coupling partner was
applied to the alkenylation reaction under the above reaction
conditions (Table 2, compounds 4a, 4b, and 4c). It was found
10
11
53
50
12
b
12
100
69
a
Reaction conditions: 1 (0.5 mmol), 2 (0.65 mmol), Pd(OAc)2 (5
mol %), 1,10-phenanthroline (30 mol %) and oxidant (1.5 equiv),
solvent (1.5 mL), 12 h. No 1,10-phenanthroline was added. Isolated
yields.
b
c
Table 2. C2-Selective Alkenylation of 4-Methylthiazole and
Thiazole
a
,b
a
Scheme 1. Substrate Scope
a
Reaction conditions: 1 (0.5 mmol), 2 (0.65 mmol), Pd(OAc)2 (5
mol %), 1,10-phenanthroline (30 mol %), and AgNO3 (1.5 equiv),
b
c
DMSO (1.5 mL), 100 °C, 12 h. Isolated yields. No 1,10-
phenanthroline was added.
that the yield of the desired product was significantly
diminished without 1,10-phenanthroline in the system. No
C5 alkenylation or dialkenylation products were observed.
To further illustrate the regioselective control of our
metholodogy, we investigated the site-selective oxidative
olefination of a more challenging substrate of the thiazole
moiety. Under the optimal reaction conditions, terminal olefin
coupling partners could couple with the C2 position of thiazole
in moderate yields whereas the C4 and C5 positions of thiazole
cannot undergo the alkenylation reaction with the excessive
alkene (Table 2, compounds 4d, 4e). No desired product was
a
Reaction conditions: 1 (0.5 mmol), 2 (0.65 mmol), Pd(OAc)2 (5
mol %), 1,10-phenanthroline (30 mol %), and AgNO3 (1.5 equiv),
DMSO (1.5 mL), 100 °C, 12 h. Isolated yields.
b
examined the compatibility of the olefin coupling partners.
Gratifyingly, terminal olefin coupling partners containing ester,
amide, and aryl moieties were found to be suitable reactants
(Scheme 1, compounds 3a−3f). Further reactions of differently
4,5-disubstituted thiazoles show the versatility of this oxidative
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Organic Letters
Letter
observed without 1,10-phenanthroline in the reaction system.
The result from the above experiment indicates that, relative to
the C4 and C5 positions in thiazoles, the C2 position should
have higher reactivity in the formation of the alkenylation
product under the optimal conditions and 1,10-phenanthroline
played an important role in the C2 selectivity inversion.
To gain insight into the reaction mechanism, we investigated
the effect of an acidic or alkaline environment on the
olefination reaction. Trifluoroacetic acid or acetic acid was
shown to be an efficient additive in the C-5 alkenylation of
electron-deficient (hetero)arenes.9,4a Unexpectedly, though, no
desired C-2 alkenylation product 3a was observed with the
addition of trifluoroacetic acid or acetic acid to the Pd(OAc)2/
AgNO3 system, whereas homocoupling product 3aa was
produced (Table 3, entries 1 to 3). Bases are reportedly used
Scheme 3. Proposed Mechanism
a
Table 3. Effect of Acidic or Alkaline Environment
palladium(II) intermediate A. Next, the resulting Pd−C bond
of A adds to the carbon−carbon double bond of the terminal
olefin coupling partners, such as methyl acrylate, to form the Pd
complexes B. Later, product 3 was formed when β-H
elimination of B occurred. However, for 1-octene,2b complexes
C may be the predominant intermediate after the formation of
intermediate A and branched product 2 was obtained. Thiazole
homocoupling proceeded through the formation of intermedi-
ate D when an acid or base was applied to the reaction system.
Further studies are needed to understand the mechanism of
selectivity between the C2 and C5 positions in a Pd-catalyzed
oxidative Heck reaction.
In summary, we have developed an efficient and highly C2
selective oxidative olefination of thiazole derivatives. The broad
substrate scope made this method synthetically useful. Further
investigations to gain insight into the reaction mechanism and
to apply this methodology to the synthesis of biologically active
molecules are underway.
yield of 3a
yield of 3aa
b
b
entry
1
acid
base
(%)
(%)
CH3COOH
(1.0 equiv)
−
−
−
trace
trace
trace
trace
trace
trace
28
2
3
4
5
6
CF3COOH
(1.0 equiv)
33
CF3COOH
(0.1 equiv)
15
−
−
−
pyridine
(1.0 equiv)
trace
24
K3PO4
(1.0 equiv)
LiOt-Bu
(1.0 equiv)
44
a
Reaction conditions: 1a (0.5 mmol), 2a (0.65 mmol), Pd(OAc)2 (5
mol %), 1,10-phenanthroline (30 mol %), and AgNO3 (1.5 equiv),
DMSO (1.5 mL), 100 °C, 12 h. Isolated yields.
ASSOCIATED CONTENT
* Supporting Information
b
■
S
Detailed experimental procedures and characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
extensively in C−H/C−H oxidative coupling reactions of
thiazoles and enhance the efficiency of C−C bond
formation.11−14 However, the addition of 1 equiv of base
13
such as LiOtBu,11 pyridine,12 and K3PO4 was detrimental to
AUTHOR INFORMATION
Corresponding Author
■
the reaction and resulted in the lack of any observable desired
thiazole olefination product. Additionally, the homocoupling
product 3aa formed when a strong base (LiOtBu and K3PO4)
was applied to the reaction system (Table 3, entries 4 to 6).
The above findings indicate that a neutral environment may be
the preferred condition for this oxidative Heck reaction of
thiazoles at the C2 position. Additionally, different results in
Table 1 between incomplete ionization salts and complete
ionization salts should be presently well understood. Moreover,
the H/D exchange control experiments for benzothiazole 1b
was performed and moderate deuterium incorporation at the
C-2 position was observed. However, no deuterium incorpo-
ration occurred when no Pd-catalyst was used (Scheme S1).
The results indicate that the thiazoles should undergo a
substitution reaction with the Pd-catalyst to generate a
thiazolylpalladium intermediate.
*E-mail: kuangcx@tongji.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21272174), the Key Projects of Shanghai in Biomedicine
(No. 08431902700), and the Scientific Research Foundation of
the State Education Ministry for Returned Overseas Chinese
Scholars. We also thank the Center for Instrumental Analysis,
Tongji University, China.
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