Copper-Catalyzed Coupling of Oxime Acetates with Isothiocyanates: A Strategy for 2-Aminothiazoles

Article abstract of DOI:10.1021/acs.orglett.5b03188

A new strategy for 2-aminothiazoles is developed via the copper-catalyzed coupling of oxime acetates with isothiocyanates. Various 4-substituted and 4,5-disubstituted 2-aminothiazoles were formed smoothly under mild reaction conditions. This process involved copper-catalyzed N-O bond cleavage, activation of vinyl sp² C-H bonds, and C-S/C-N bond formations. It is noteworthy that the oxime acetates were used not only as a substrate but also as a single oxidant.

Full text of DOI:10.1021/acs.orglett.5b03188

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Coupling of Oxime Acetates with Isothiocyanates:
A Strategy for 2‑Aminothiazoles
Xiaodong Tang, Zhongzhi Zhu, Chaorong Qi, Wanqing Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A new strategy for 2-aminothiazoles is developed via the
copper-catalyzed coupling of oxime acetates with isothiocyanates. Various 4-
substituted and 4,5-disubstituted 2-aminothiazoles were formed smoothly
under mild reaction conditions. This process involved copper-catalyzed N−O
bond cleavage, activation of vinyl sp2 C−H bonds, and C−S/C−N bond
formations. It is noteworthy that the oxime acetates were used not only as a
substrate but also as a single oxidant.
n the past few decades, transition-metal-catalyzed oxidation
reactions have been a good method for carbon−carbon and
pyrroles, imidazo[1,2-a]pyridines, pyrazoles, and pyridines via
copper-catalyzed coupling reactions with oxime esters as the
substrates (Scheme 1a−d).12 Herein, we report a novel method
I
carbon−heteroatom bond formations.1 However, the use of the
external oxidants makes these reactions suffer from harsh
reaction conditions, poor functional group tolerance, and the
waste of the reduced external oxidant. To solve this problem,
attention has shifted to the internal oxidants.2 The reactions
which utilize internal oxidants are redox-neutral and do not
require external oxidants. While the N−N,3 N−S,4 and N−
O5−7 bonds were all used as internal oxidants, the N−O bond
is the most common. Narasaka et al. seminally studied
palladium-catalyzed intramolecular Heck-type cyclization of
oxime derivatives, and other groups recently reported
palladium-catalyzed C−H functionalizations which use the
N−O bond as the internal oxidant.5 In addition, the N−O
bond cleavage was also used as the oxidant in ruthenium- and
rhodium-catalyzed reactions.6,7 These reactions utilizing
internal oxidants have many advantages, such as mild reaction
conditions, high selectivity, and good functional group
tolerance. Thus, it is meaningful and desirable to apply internal
oxidants in more transition-metal-catalyzed oxidation coupling
reactions.
Scheme 1. Our Previous Work and This Work
The 2-aminothiazole motif has been widely used in medicinal
chemistry.8 Until now, one of the most common methods for
the synthesis of 2-aminothiazoles has been the Hantzsch
reaction, which uses α-halocarbonyl compounds to couple with
thioureas.9 Recently, reactions directly starting from ketones
and thioureas have been also reported for synthesis of 2-
aminothiazole.10 However, they suffer from harsh reaction
conditions, poor functional group tolerance, or limited starting
materials. Therefore, it is desirable and challenging to develop
more green reagents and new routes for 2-aminothiazoles. An
oxime ester, which comes from the esterification of oxime, is
cheap and readily available.11 In recent years, we and other
groups have found that oxime esters were good synthons for
nitrogen-bearing heterocyclic compounds in the presence of a
copper catalyst,12,13 and oxime esters were used not only as
substrates but also as oxidants. We have developed a series of
methods for the synthesis of N-heterocycle compounds such as
for 2-aminothiazoles via the copper-catalyzed oxidative
coupling of oxime acetates with isothiocyanates using N−O
bonds as the internal oxidant; thus, there is no need for
additional oxidants (Scheme 1e).
At the start of our studies, we used acetophenone oxime
acetate (1a) and phenyl isothiocyanate (2a) as models to
screen bases, copper salts, and solvents, and the results are
summarized in Table 1. Initial attempts were performed with a
catalytic amount of CuI, K2CO3 as base, and toluene as solvent
under an air atmosphere. We were excited that the unpredicted
product N,4-diphenylthiazol-2-amine (3aa) was obtained in
Received: November 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03188
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Cu(I)-Catalyzed Synthesis of 2-Aminothiazoles
from Various Oxime Acetates and Phenyl Isothiocyanate
a
b
entry
[Cu]
CuI
base
solvent
toluene
yield (%)
1
K2CO3
Na2SO3
NaHSO3
KOtBu
DBu
14
2
CuI
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
23
3
CuI
13
4
CuI
43
5
CuI
15
6
CuI
Cs2CO3
−
84 (80)
n.d.
n.d.
42
7
CuI
8
−
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
CuCl
CuBr
CuCl2
CuBr2
Cu(OAc)2
Cu(OTf)2
CuI
10
11
12
13
14
15
16
17
79
12
14
69
67
n.d.
n.d.
48
CuI
a
CuI
1,4-dioxane
toluene
The reactions were carried out at 105 °C using 1 (0.5 mmol), 2a (0.5
c
18
CuI
82
mmol), CuI (20 mol %), and Cs2CO3 (0.25 mmol) in toluene (3 mL)
under air for 8 h. Yields refer to the isolated yields.
a
Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.5 mmol), 2a (0.5 mmol), base (0.25 mmol), and
[Cu] (20 mol %), in toluene (3 mL) at 105 °C under air for 8 h.
an electron-donating group showed higher reactivity than those
with an electron-withdrawing group. Unfortunately, a strong
electron-withdrawing group such as nitro was not applicable in
this transformation. It is worth noting that the disubstituted
acetophenone oxime acetates were a suitable substrate, and the
corresponding products were formed in 81% and 70% yields,
respectively (3ma, 3na). Notably, a heteroaryl-bearing oxime
acetate was also compatible for this transformation and
transferred to the corresponding product in 75% yield (3oa).
More importantly, the strategy was also available for the
construction of 4,5-disubstituted 2-aminothiazoles in good
yields (3pa−3wa).
Next, the scope of isothiocyanates was examined for this
reaction (Scheme 3). For various para-substituted phenyl
isothiocyanates with electron-donating or -withdrawing sub-
stituents on the aromatic ring, the reactions proceeded
smoothly to afford the desired products 3ab−3af in good
yields. When 3-methylphenyl isothiocyanate was used, product
3ag was isolated in 77% yield. It is worth mentioning that the
annulation reaction could be expanded to alkyl and benzyl
isothiocyanates, and the corresponding products could be
formed in 90%, 73%, and 85% yields, respectively (3ah−3aj).
To gain more insight into the reaction mechanism, we added
the radical scavenger TEMPO or BHT to our standard reaction
[eqs 1 and 2]. When TEMPO was added, the reaction system
was very complex and no product was detected. In addition,
acetophenone was obtained in 18% yield and acetophenone
oxime acetate was recovered in 11% yield [eq 1]. When BHT
was added, the conditions were similar to the case with
TEMPO; acetophenone was obtained in 10% yield and
acetophenone oxime acetate was recovered in 35% yield [eq
2]. When phenyl isocyanate was added to the reaction, the
corresponding product 4 was not detected [eq 3].
b
Determined by GC and dodecane as internal standard. Number in
c
parentheses is yield of isolated product. Under N2 atmosphere.
14% GC yield (Table 1, entry 1). Various bases, such as
Na2SO3, NaHSO3, KOtBu, DBU, and Cs2CO3, were examined
(entries 2−6). To our delight, Cs2CO3 gave a satisfactory yield
(84% GC yield and 80% isolated yield). Without a base or
catalyst, there was no product detected (entries 7−8). Different
copper salts such as CuCl, CuBr, CuCl2, CuBr2, Cu(OAc)2, and
Cu(OTf)2 could also catalyze this reaction (entries 9−14).
When we used DMSO and DMF as solvents, the desired
product was not detected and acetophenone oxime acetate was
found to be decomposed into acetophenone oxime and
acetophenone (entries 15−16). However, we could obtain a
moderate yield when using 1,4-dioxane as solvent (entry 17).
When the reaction was performed under a N2 atmosphere, the
result was the same as that under an air atmosphere (entry 18).
In order to simplify the operation, we elected to carry out our
process under an air atmosphere. Thus, the optimal catalytic
system for this copper-catalyzed oxidative coupling reaction was
as follows: 1a (0.5 mmol), 2a (0.5 mmol), CuI (20 mol %), and
Cs2CO3 (0.25 mmol) in toluene (3 mL) at 105 °C under air for
8 h.
With the optimized reaction conditions in hand, the
generality of this copper-catalyzed oxidative coupling of
oxime acetates with isothiocyanates was examined. The scope
of the oxime acetates was first explored by the adoption of
phenyl isothiocyanate as the coupling partner, and the results
are summarized in Scheme 2. Both electron-rich (H, 1a; CH3,
1b; OMe, 1f) and electron-poor (halogen, 1c−e) para-
substituted acetophenone oxime acetates participated well in
this reaction, and the desired products were formed in good
yields. In addition, the substrates with a fluoro, chloro, bromo
group at the meta- or ortho-position could also react smoothly
to afford the corresponding products with good to excellent
yields (3ga−3la). In general, acetophenone oxime acetates with
Based on previous works on copper-catalyzed transformation
of oxime esters and our control experiment, a possible
mechanism is proposed in Scheme 4.12−16 First, iminium
radical A was produced via reduction by CuI.12−14 The free-
B
DOI: 10.1021/acs.orglett.5b03188
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Letter
and isomerization (path b).16 Subsequently, the intermediate D
was oxidized by CuII to give the intermediate E. Finally, the
desired product 3aa was obtained by deprotonation and the
resulting acid was neutralized by the base.
Scheme 3. Cu(I)-Catalyzed Synthesis of 2-Aminothiazoles
from Acetophenone Oxime Acetate and Various
Isothiocyanates
a
In summary, an efficient and external-oxidant-free 2-amino-
thiazole synthesis from copper-catalyzed oxidative coupling of
oxime acetates with isothiocyanates has been developed.
Importantly, the reaction was accomplished through N−O
bond cleavage, and new C−S/C−N bond formations, along
with the activation of vinyl sp2 C−H bonds under mild
conditions. Various 4- and 4,5-substituted 2-aminothiazoles
were formed in good yields. Further studies on this topic are
currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03188.
Typical experimental procedure and characterization for
all products (PDF)
a
The reactions were carried out at 105 °C using 1a (0.5 mmol), 2 (0.5
AUTHOR INFORMATION
Corresponding Author
mmol), CuI (20 mol %), and Cs2CO3 (0.25 mmol) in toluene (3 mL)
under air for 8 h. Yields refer to the isolated yields.
■
*E-mail: jianghf@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21172076 and 21420102003), and the Fundamental
Research Funds for the Central Universities (2015ZY001) for
financial support.
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