Pd/Cu-cocatalyzed reigoselective arylation of thiazole derivatives at 2-position under ligand-free conditions

Article abstract of DOI:10.1039/c5ra08703a

An efficient protocol for regioselective arylation of thiazole derivatives at the 2-position via palladium- and copper-catalyzed C-H bond activation under ligand-free conditions has been developed. The reaction proceeds smoothly with 1% palladium catalyst in the presence of 20% Cu(TFA)₂ to furnish the desired products. The direct C-H arylation and no ligand made this method synthetically useful for the arylation of thiazoles at the 2-position.

Full text of DOI:10.1039/c5ra08703a

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Pd/Cu-Cocatalyzed Regioselective Arylation of
Thiazole Derivatives at 2-Position under Ligand-Free
Conditions
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Jian Gu, Chun Cai *
DOI: 10.1039/x0xx00000x
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arylation of thiazole-containing structural motifs and even some
examples have been achieved in a regioselective manner.[8] In
general, 2-blocked thiazoles were used to get the selective 5-arylated
thioazoles, and the 5-substituted thiazoles were employed to achieve
2-arylated thiazole derivatives.[9] Moreover, the reported protocols
have some drawbacks such as the use of air- and moisture-sensitive
Pd(PPh3)4 or an additional ligand.[10] Many groups have accom-
plished excellent results that address the drawbacks mentioned above
in the arylation of thiazoles.[11] In these methods, 4-methylthiazole
was rarely used because 4-methylthiazole dimer was more easily
formed than thiazole dimer.[12] 5-arylated thioazole and 4-
methylthiazole dimer should be reduced simultaneously to get the
selective 2-arylated thioazole. On the basis of the above excellent
works, our attention was drawn to the observation that copper salts
can affect the regioselectivity of palladium-catalyzed electron-rich
heterocycle arylation. To our delight, we found that when a
combination of catalytic Pd and Cu was used, the main products
were 2-arylated thiazole derivatives.
An efficient protocol for regioselective arylation of thiazole
derivatives at 2-position via palladium- and copper- catalyzed
C-H bond activation under ligand-free conditions has been
developed. Reaction proceeds smoothly with 1% palladium
catalyst in the presence of 20% Cu(TFA)2 to furnish the
desired products. The direct C-H arylation and no ligand
used made this method synthetically useful for the arylation
of thiazoles at the 2-position.
As an efficient and green method, direct C-H functionalization has
been focused on because of its high atom efficiency and minimized
wasteful byproducts compared to the reported cross-coupling
reactions and its wide range of applications in the synthesis of
biologically active compounds and organic intermediates.
Transition-metal-catalyzed C−H functionalizations are some of the
most convenient and efficient procedures available for the
construction of complex heterocycles from simple starting
materials.[1] At the same time, arylation of heterocycles has received
significant attention in recent years because the heteroarenes are
important structural units frequently found in biologically active
molecules, organic materials, and pharmaceuticals.[2] Consequently,
there has been significant effort at achieving efficient, high yielding,
and highly selective functionalization of these types of molecules.[3]
Traditional cross-coupling methodologies are highly versatile, but
they need preactivation of heterocycles.[4] Therefore, the more
efficient routes to these compounds involve direct functionalization
of heterocycle C-H bonds were applied for the arylation reactions.
Scheme
1
Pd/Cu-Cocatalyzed Regioselective Arylation of Thiazole
Derivatives
The Pd/Cu-cocatalyzed regioselective C-H arylation of 4-
methylthiazole (1) with iodobenzene (2a) was chosen as model
reaction for the purpose of optimization of reaction conditions. Since
the reaction proceeded smoothly to afford the desired 2-phenylated
4-methylthiazole (3a) in the presence of a combination of catalytic
Pd and Cu, various palladium and copper catalysts were screened for
the selective C-H arylation reaction. It has been observed that, 5a
and 6a increased as the main byproduct respectively when CuI or
the combination of CuI and Pd(OAc)2 was used as the catalyst
(Table 1, entries 10 and 11). The yield of 3a decreased dramaticly in
the absence of copper or palladium source, indicating that copper
However the selectivity of C-H bond is one of the eternal research
topics in organic synthesis.[5] Current solutions to achieve the
selective functionalization among multiple C-H bonds that exist in
the substrates and products usually are constructing a directing group
or distinguishing C-H bonds by their inherent electronic nature.[6]
However, there are some disadvantages of directing group strategy,
for example, the directing groups are not always desirable in the
target molecule and the removal of them is obligatory.[7] Therefore,
regioselective arylation of heterocycles is highly desirable for
practical synthetic application.To solve the problem, significant
developments to carry out C-H activations have enabled direct
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and palladium sources were crucial for the reaction (Table 1,entries amount for the catalysts. Subsequent experiments revealed that 3h
8-9). Therefore, the combination of Pd(OAc)2 and Cu(TFA)2 has was ideal reaction time to reach better yield of 3a. (Table 1, entries
shown a good catalytic activity among all the above catalysts 1-6). The addition of 2.0 equiv t-BuOLi greatly improved the
combination, providing the desired product in up to 81% yield reaction yield from 40% to 81% yield (Table 1, entries 6 and 15).
(Table 1, entry 6). When the loading of Pd(OAc)2 increased from 1% Other inorganic bases such as, t-BuONa, t-BuOK, Cs2CO3 and KOH
to 5%, the yield of 3a decreased because 4a, 5a and 6a were were less effective than t-BuOLi (Table 1, entries 16-19). Solvent
produced simultaneously as byproducts (Table 1, entries 6 and 7). screening indicated that polar aprotic DMF was the best choice
Therefore, 1% Pd(OAc)2 with 20% Cu(TFA)2 was the optimal (Table 1, entries 13-14).
Table 1. Optimizing the Reaction Conditionsa
Entry
Time/h
Catalyst (mol %)
Solvent
Base
Yield/(%)
3a
54
68
70
73
80
81
20
5
4a
1
5a
--
2
6a
--
--
--
--
--
--
10
--
--
--
1
0.5
1
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (5), Cu(TFA)2 (20)
Pd(OAc)2(1)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
DMF
DMF
DMF
DMF
DMF
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
--
2
5
3
1.5
2
9
2
4
10
12
13
28
31
--
2
5
2.5
3
3
6
3
7
3
18
--
--
33
--
15
8
8
3
9
3
Cu(TFA)2 (20)
--
10
11
12
13
14
15
16
17
18
19
3
CuI (20)
30
63
46
68
31
40
34
18
6
--
3
Pd(OAc)2 (1), CuI (20)
--
17
3
Pd(OAc)2 (1), Cu(OAc)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
Pd(OAc)2 (1), Cu(TFA)2 (20)
10
15
--
--
--
--
--
--
--
--
--
3
3
--
20
--
--
--
--
3
--
3
t-BuOK
t-BuONa
Cs2CO3
KOH
--
3
30
13
--
3
3
--
a Reaction condition: 1a (1.0 mmol), 2a (1.0 mmol), base(2 equiv), in solvent(3 mL). The yields were determined by GC.
Under the optimized conditions, the scope of this selective C-H with satisfactory yields. It is noteworthy that the para-methyl, para-
arylation reaction was investigated with different aryl iodide. Either chloro, para-nitro groups were very compatible, producing the
electron-withdrawing or electron-donating groups on the phenyl ring corresponding products in good yields (3d-3g). However, when
of the aryl iodide were well tolerated, affording the desired products sterically hindered substrates such as ortho-methyl iodobenzene,
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ortho- carboxyl iodobenzene were employed in the reaction, the
yield of 3b and 3i dramatic declined, and the significant differences
between the yields of 3b and 3i may be due not only steric hindrance
but also the electron-donating or electron-withdrawing characters of
the substituents. Di-4-methylthiazole compound 3h was obtained as
main product when 1,4-diiodobenzene was used. Unfortunately, no
desired products were obtained when bromobenzene and
chlorobenzene were employed under the optimal reaction conditions.
Based on our investigations and previous study by some
groups[11b,13], the catalytic pathway is considered to proceed as
shown in Figure 1. After the reduction of the Pd(II) species to a Pd(0)
species (this might be stabilized by the starting thiazole moiety or
the corresponding product), arylpalladium species 9 is generated.
Because of the ability of Cu salts to metallate acidic C-H bonds and
in particular the C-2 position of thiazole moiety, in the presence of a
base ， organocopper derivatives 10 will be produced and CuX
oxidized to Cu(II) in the presence of air, might then undergo
transmetallation with the aryl palladium(II) halide species 9,
reductive elimination occurs to afford the desired biaryl product 3 by
releasing the Pd(0) species to complete the catalytic cycle.
Table 2. Substrate Scope of Regioselective Arylation of 4-
methylthiazole a
Table 3. Substrate Scope of Regioselective Arylation of
Benzothiazole a
3a,75%
3d,70%
3f,85%
3bb,56%
3c,71%
8a,78%
8d,92%
8f,90%
8bb,64%
8c,76%
3e,68%
3g,88%
8eb,74%
8g,78%
3hc,70%
3i,trace
8i,trace
a
Reaction condition: 1 (1.0 mmol), 2 (1.0 mmol),Pd(OAc)2
(1 mol%), Cu(TFA)2 (20 mol%), t-BuOLi (2 equiv), in DMF(3.0
c
mL), 3 h. Isolated yield.b Reaction time was 5 h. 2 equiv 4-
a
Reaction condition: 1 (1.0 mmol), 2 (1.0 mmol),Pd(OAc)2
(1 mol%), Cu(TFA)2 (20 mol%), t-BuOLi (2 equiv), in DMF(3.0
mL), 3 h. Isolated yield. b Reaction time was 5 h.
methylthiazole was used.
To expand the substrate scope, benzothiazole was examined with
different iodobenzene under the optimized conditions. The steric
effect and electronic effect were the same as 4-methylthiazole.
However, the yield of benzothiazole was generally higher than 4-
methylthiazole because of the less byproduct. However when 1,4-
diiodobenzene was employed in the reaction, 8a was obtained rather
than the corresponding monosubstituted or disubstituted product. It
may be due to the formation of monosubstituted product which can
easily dehalogenate in alkalis condition.
Conclusions
In summary, an efficient protocol for regioselective arylation of
electron-rich thiazole derivatives at 2-position via palladium- and
copper- catalyzed C-H bond activation has been developed. The less
usage of palladium and ligand-free conditions make this C-H
arylation protocol more resourceful for future applications and
provide a powerful tool for the synthesis of substituted arylthiazole
derivatives.
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Notes and references
Chemical Engineering College, Nanjing University of Science &
*
Technology, Nanjing, Jiangsu 210094, P. R. China
E-mail: c.cai@mail.njust.edu.cn.
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