Selective Formation of 2-(2-Aminophenyl)benzothiazoles via Copper-Catalyzed Aerobic C?C Bond Cleavage of Isatins

Article abstract of DOI:10.1002/adsc.201901670

Herein, two kinds of structurally significant 2-(2-aminophenyl)benzothiazoles were selectively generated by the copper-catalyzed aerobic C?C bond cleavage of isatins. Morpholine served not only as a reactant but a promoter in the three-component assembly of 2-(2-aminophenyl)benzothiazoles. Also it proved to be an efficient additive for the formation of free amino 2-(2-aminophenyl)benzothiazoles. This protocol represents a step-economic entry to the title compounds with a range of compatible functionalities. (Figure presented.).

Full text of DOI:10.1002/adsc.201901670

Title: Selective Formation of 2-(2-Aminophenyl)benzothiazoles via
Copper-Catalyzed Aerobic C-C Bond Cleavage of Isatins
Authors: Hongfen Wang, Zhenhua Xu, Guojun Deng, and Huawen
Huang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901670
Link to VoR: http://dx.doi.org/10.1002/adsc.201901670

10.1002/adsc.201901670
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Selective Formation of 2-(2-Aminophenyl)benzothiazoles via
Copper-Catalyzed Aerobic C-C Bond Cleavage of Isatins
Hongfen Wang,a Zhenhua Xu,a Guo-Jun Deng,a,b Huawen Huang*,a
a Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly
Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China
E-mail: hwhuang@xtu.edu.cn.
b Beijing National Laboratory for Molecular Sciences, Chinese Academy of Sciences (CAS), Beijing 100190, China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please delete
if not appropriate))
uncovered to provide convenient accesses to substituted
thiazoles.[7] Alternatively, the powerful cross couplings
Abstract. Herein, two kinds of structurally significant 2-(2-
aminophenyl)benzothiazoles were selectively generated by
by transition metal catalysis have been used for the late
the copper-catalyzed aerobic C-C bond cleavage of isatins.
stage modification of thiazoles.[8]
Morpholine served not only as a reactant but a promoter in
the
three-component
assembly
of
2-(2-
aminophenyl)benzothiazoles. Also it proved to be an
efficient additive for the formation of free amino 2-(2-
aminophenyl)benzothiazoles. This protocol represents a
step-economic entry to the title compounds with a range of
compatible functionalities.
Keywords: copper catalysis; aerobic oxidation; 2-(2-
aminophenyl)benzothiazoles; chemoselectivity; isatins
Scheme 1. Examples of benzothiazole applications.
Thiazole is one of structurally privileged motifs in
heterocycle compounds and constitutes the key units of
numerous biologically active compounds including
pharmaceuticals[1] and naturally occurring products.[2]
Benzothiazole frameworks have been found to be the
key units of a range of potent antitumor agents (Scheme
1).[3] In the last few decades, organic functional materials
containing thiazole moiety have also attracted
considerable interest.[4] For example, terarylene
frameworks containing benzothiazoles were recently
used as a photoprecursor of hydride donors.[5]
Particularly, due to its highly fluorescent properties
(Scheme 1), 2-(2-aminophenyl)benzothiazole (ABT) and
its derivatives were used as new sensitive and selective
fluorescent probes for phosgene, H2S, and photodynamic
therapy.[6] In light of these utilities, the development of
synthetic methods for thiazole construction has been
extensively studied. The traditional thiazole formation
mainly relies on classic Hantzsch thiazole synthesis
which refers to the condensation annulations of α-
haloketones and thioureas or thioamides. Over the past
years, a number of novel cyclization reactions have been
Given the diverse synthetic methods for substituted
thiazoles, the most effective synthetic method for
benzothiazoles remains the cyclocondensation of 2-
aminobenzenethiol with carboxylic acids. Other C1
compounds such as aldehydes, alcohols, and methyl
(hetero)arenes etc. could also be employed.[9] Despite of
the practical effectiveness, those methods suffer from
limitations with respect to strong acidic conditions, high
reaction temperature, and excessive amounts of oxidant
required. More importantly, some synthetically and
pharmaceutically useful functionalities such as amino
could not be tolerated in these harsh systems. To access
functional 2-(2-aminophenyl)benzothiazoles, a step-wise
process is generally required, whereby nitro-containing
substrates are initially utilized. Hence, the mild
construction of fused thiazoles from simple raw
materials[10] by sustainable aerobic oxidation[11] is highly
desirable. Herein, we report on the facile copper-
catalyzed aerobic systems which enable the
straightforward
generation
of
2-(2-
aminophenyl)benzothiazoles using isatins as the
coupling partner. In our protocol, isatins proceed through
1
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10.1002/adsc.201901670
Advanced Synthesis & Catalysis
an oxidative C-C bond cleavage to provide an effective
formal amino-attached C1 source. Moreover, two kinds
of 2-(2-aminophenyl)benzothiazoles are selectively
generated by the key control of copper catalysts.
Catalyst
Equiv Temp.
4a
5a
Entry
1
2
3
4
5
6
7
CuCl2
CuCl2
Cu(acac)2
Cu(OAc)2
CuBr2
CuCl
CuI
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl2
CuCl2
CuBr
-
-
130
130
130
130
130
130
130
130
130
130
130
120
140
130
130
130
130
130
-
15
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
2.5
2.5
2.5
1.0
1.0
2.5
1.0
1.0
trace 56
30
trace 28
-
While 1H-benzo[d][1,3]oxazine-2,4-dione could also
be used as a formal amino-attached C1 coupling partner,
we initially chose the bench-stable isatin (1a) and 2-
aminobenzenethiol (2a) as the model substrates to screen
the reaction conditions (Table 1). To our delight, the
mixture of reactants with the CuCl2 catalyst in DMSO
was performed under oxygen atmosphere at 130 °C to
give the target 2-(2-aminophenyl)benzothiazole 5a in 15%
yield (entry 1). Then, the addition of morpholine (3a, 1.0
equiv) dramatically enhanced the formation of 5a to 56%
yield, along with a three-component reaction to deliver
the product 2-(2-aminophenyl)benzothiazole 4a (entry 2).
The structure of 4a was confirmed by single-crystal X-
ray diffraction analysis.[12] Next, we screened a series of
copper catalysts. While Cu(acac)2 and Cu(OAc)2
exclusively gave 5a (entries 3 and 4), other copper salts
such as CuBr2, CuCl, and CuI led to a mixture of 4a and
5a with poor chemoselectivity (entries 5-7). We then
found that the use of CuBr as the catalyst turned the
selectivity over the formation of 4a, along with only
trace amounts of 5a (entry 8). We suspected that
morpholine (3a) played not only as a substrate but also a
trigger to promote the C-C bond cleavage. Indeed, the
yields of 4a increased with the amounts of 3a increased
(entries 8-10), and 2.5 equiv of morpholine gave the best
result (70% yield, entry 11). Lowering the reaction
temperature to 120 °C gave an obviously diminished
yield of 4a (entry 12), while the reaction at elevated
temperature had no benefit to the three-component
reaction (entry 13). With respect to the formation of free
amino product 5a, while CuCl2 was used as the optimal
catalyst, when the catalyst loading decreased to 5 mol%
with prolonged reaction time to 24 h, the product was
formed in 74% yield (entry 14). The oxygen-free control
experiments for both catalytic systems revealed that
oxygen played an essential role for the generation of
both benzothiazole products (entries 15 and 16). Finally,
the reaction in the absence of copper catalysts or using
elemental iodine as the catalyst did not afford any
benzothiazole product (entries 17 and 18).
23
15
21
35
41
59
70
52
68
35
40
37
trace
trace
trace
trace
trace
trace
8
9
10
11
12
13
14[c]
15[d]
16[d]
17
18
trace 74
-
-
-
-
-
-
trace
-
I2
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3a,
catalyst (10 mol %), DMSO (1.0 mL), under O2
(sealed tube) for 12 h.
[b] Isolated yield.
[c] Catalyst (5 mol %) within 24 h..
[d] Under Ar atmosphere.
With the optimized reaction conditions in hand, we
next explored the substrate scope of both reaction
systems. For the three-component aerobic benzothiazole
formation (Scheme 2), the copper catalysis was
documented to be gram-scalable and the 10 mmol scale
reaction gave 4a in 71% yield, thus revealing the robust
nature of the aerobic copper catalysis. 5-Methyl and 5-
methoxyl isatins afforded the corresponding products in
moderate yields (4b, 4c, 61% and 64%, respectively).
Halogen functionalities such as F, Cl, and Br could be
tolerated, albeit with lower yields (4d-4f, 4i-4k).
Presumably due to the effect of steric hindrance, C7-
substituted isatins afforded the desired benzothiazole
products in lower yields (4h-4k). Regarding substituted
2-aminobenzenethiols, the expected products were
obtained in generally moderate yields with compatible
synthetically useful halo and methoxy (4l-4o). The
secondary amine component was limited to morpholine
and thiomorpholine, which produced the desired
products in good yields (4p, 4q, 68% and 66%,
respectively). Unexpectedly, trace amounts of products
were detected when other cyclic and acyclic secondary
amines such as piperidine, pyrrolidine, and dibutylamine
were used in the present system. We have no idea about
the big reactivity difference of these amines.
Table 1. Optimization of Reaction Conditions[a]
Yield[b]
3a
2
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10.1002/adsc.201901670
Advanced Synthesis & Catalysis
Scheme 3. Copper-catalyzed aerobic formation of free 2-
(2-aminophenyl)benzothiazoles.
With the established reactivities of the aerobic copper
catalysis, we were attracted to depicting action model of
this facile system. To this end, a series of control
experiments were performed (Scheme 4). The treatment
of isatin (1a) and 2-aminobenzenethiol (2a) in the
absence of morpholine (3a) under Ar afforded only trace
amounts of the spiro product 6, while the addition of 3a
dramatically improved this condensation transformation
(Scheme 4, a). The combination of 1a and 3a without 2a
under Ar delivered 2-morpholino-3H-indol-3-one (7) as
the main product (Scheme 4, b). Notably, the
intermediates 6 and 7 were only detected by GC-MS. We
tried to isolate them, but we failed. We suspect both of
them are unstable since we only got complex mess after
column chromatography. Subsequently, bis-condensation
spiro product 8 was detected by GC-MS when the model
three-component reaction was performed under Ar
(Scheme 4, c). These results indicated that the amine
component could selectively couple with carbonyl sites
of 1a. Then, when 1H-benzo[d][1,3]oxazine-2,4-dione
(9), which may be generated in situ in the aerobic copper
catalysis, was subjected to the present systems, no
desired benzothiazole product was formed (Scheme 4, d).
Finally, the addition of radical scavenger such as
TEMPO and BHT into the systems proved to be no
obvious prohibiting effect on the yield (Scheme 4, e),
which revealed that the copper-catalyzed aerobic
reactions may not proceed through a radical pathway.
Scheme 2. Copper-catalyzed aerobic three-component
a
formation of 2-(2-aminophenyl)benzothiazoles. Yield
of 10 mmol scale reaction.
In line with the production of model substrates in both
copper catalysis systems, the reaction yields of free
amino benzothiazoles were generally higher than the
three-component benzothiazoles (Scheme 3). For
example,
halo-attached
isatins
furnished
the
corresponding 2-(2-aminophenyl)benzothiazoles in
moderate to good yields. Hence, F, Cl, and Br functional
groups were accommodated with this reaction system
(5d-5f, 5i-5k). Other compatible functionalities included
methyl and methoxy. Once again, substituted 2-
aminobenzenethiols were subjected to the aerobic copper
catalysis, which afforded the target benzothiazoles with
substituents attached at C4, C5, and C6 positions (5l-5p).
We suspected that the compound 4 could be used as a
fluorescent probes for H2S detection since the product 4a
has no fluorescent properties.[6b] But when we treated it
with Na2S, 4a did not decompose into to 5a even in a
high temperature.
3
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10.1002/adsc.201901670
Advanced Synthesis & Catalysis
control of copper catalysts and the amounts of
morpholine additive/reactant. This protocol provides a
straightforward
aminophenyl)benzothiazole
entry
to
valuable
compounds
2-(2-
from
inexpensive and bench-stable starting materials. The
low-cost copper catalysts and sustainable oxygen were
used to constitute the facile and viable reaction systems
for the desired transformation.
Experimental Section
General procedure for the synthesis of benzothiazole
heterocycles
General procedure A: Indoline-2,3-dione (1a, 29.4 mg, 0.2
mmol), 2-aminobenzenethiol (2a, 43 µL, 0.4 mmol), and
morpholine (3a, 44 µL, 0.5 mmol), CuBr (2.9 mg, 0.02mmol,
10 mol %), and DMSO (1.0 mL) were added successfully to a
10 mL oven-dried reaction vessel. The sealed reaction vessel
was stirred under O2 at 130 °C for 12 h. After cooling to room
temperature, the reaction was diluted with ethyl acetate (10
mL) and washed with saturated sodium chloride solution. The
organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (10 mL) for three times. The
combined organic layer was dried over magnesium sulfate and
the volatiles were removed under reduced pressure. The
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate) to yield the desired product N-
(2-(benzo[d]thiazol-2-yl)phenyl)morpholine-4-carboxamide
(4a).
Scheme 4. Control experiments.
In the current stage, the roles of both copper catalysts
how to switch the chemoselectivity are not clear. On the
basis of experimental results above, a possible reaction
pathway for the three-component benzothiazole
formation was illustrated (Scheme 5). The initial step
should be the condensation process of 1a and 3a, which
is reversible and generates imino cation A. Nucleophilic
attack of another molecular 3a to A affords intermediate
B, which then decomposes into C via dehydration. The
activated carbonyl, i.e. imino cation site, is attacked by
the bis-nucleophile 2a and releases morpholine 3a to
give the key intermediate D. With the assistance of
copper catalyst and oxygen, the C-C cleavage of D
occurs to afford the final product 4a.
General procedure B: Indoline-2,3-dione (1a, 29.4 mg, 0.2
mmol), 2-aminobenzenethiol (2a, 43 µL, 0.4 mmol),
morpholine (17 µL, 0.2 mmol), CuCl2 (1.3 mg, 0.01mmol, 5
mol %), and DMSO (1.0 mL) were added successfully to a 10
mL oven-dried reaction vessel. The sealed reaction vessel was
stirred under O2 at 130 °C for 24 h. After cooling to room
temperature, the reaction was diluted with ethyl acetate (10
mL) and washed with saturated sodium chloride solution. The
organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (10 mL) for three times. The
combined organic layer was dried over magnesium sulfate and
the volatiles were removed under reduced pressure. The
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate) to yield the desired product 2-
(benzo[d]thiazol-2-yl)aniline (5a).
Acknowledgements
Support by the National Natural Science Foundation of
China (21602187), the Science and Technology Planning
Project of Hunan Province (2019RS2039), and the
Collaborative Innovation Center of New Chemical
Technologies for Environmental Benignity and Efficient
Resource Utilization is gratefully acknowledged.
Scheme 5. Possible reaction mechanism.
In summary, we have developed chemoselective
copper-catalyzed benzothiazole formation by the key
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Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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[12]
CCDC-1917653
contains
the
supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
6
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10.1002/adsc.201901670
Advanced Synthesis & Catalysis
COMMUNICATION
Selective
Formation
of
2-(2-
Aminophenyl)benzothiazoles
via
Copper-
Catalyzed Aerobic C-C Bond Cleavage of
Isatins
Adv. Synth. Catal. Year, Volume, Page – Page
Hongfeng Wang, Zhenhua Xu, Guo-Jun Deng,
Huawen Huang
7
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