Iron-catalyzed 2-acylbenzothiazole formation from aryl ketones and benzothiazoles using oxygen as oxidant

Article abstract of DOI:10.1016/j.tetlet.2013.05.050

A convenient and efficient method for the synthesis of 2-acylbenzothiazoles from benzothiazoles and aromatic ketones using oxygen as oxidant is described. FeCl₃·6H₂O showed the best reactivity among the various iron salts investigated. Various functional groups were well tolerated under the optimized reaction conditions.

Full text of DOI:10.1016/j.tetlet.2013.05.050

Tetrahedron Letters 54 (2013) 3838–3841
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron-catalyzed 2-acylbenzothiazole formation from aryl ketones and
benzothiazoles using oxygen as oxidant q
⇑
Saiwen Liu, Ru Chen, Hui Chen, Guo-Jun Deng
Key Laboratory for Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient method for the synthesis of 2-acylbenzothiazoles from benzothiazoles and
aromatic ketones using oxygen as oxidant is described. FeCl3Á6H2O showed the best reactivity among
the various iron salts investigated. Various functional groups were well tolerated under the optimized
reaction conditions.
Received 1 March 2013
Revised 18 April 2013
Accepted 10 May 2013
Available online 18 May 2013
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Iron
Aryl ketones
Benzothiazoles
Oxygen
2-Substituted benzothiazoles are one of the most important
classes of heterocycles and have shown a wide range of biological
activities, such as antitumor, antiviral, and antimicrobial.1 In recent
years, preparation and functionalization of substituted benzothiaz-
oles have attracted much attention and great progress has been
made especially for the important class of 2-arylbenzothiazoles.2
Compared to the great progress which has been made on 2-aryl-
benzothiazole synthesis, 2-acylbenzothiazoles are rarely synthe-
sized due to the difficulty in introducing an acyl group at the 2-
position of benzothiazoles. Only a few methods have been reported
for the synthesis of 2-acylbenzothiazoles from 2-aminothiophenols
and nitriles or phenylacetaldehydes.3
Aryl alkyl ketones are cheap, commercially available, and are
widely used as intermediates for pharmaceuticals. In recent years,
the functionalization of C–H bond adjacent to the carbonyl group
has attracted great attention. Efficient methods have been devel-
oped for selective arylation or amination of aryl alkyl ketones cat-
alyzed by transition metals.4,5 Direct amidation of aryl methyl
and acetophenone as well as arylethenes, arylacetylenes, 2-hydro-
xy-aromatic ketones, and carbinols in the presence of stoichiome-
tric amounts of I2.8 In these transformations, the sp3 C–H bond
adjacent to the carbonyl group was firstly iodized before further
conversion into reactive arylglyoxal intermediate. The preparation
of 2-acylbenzothiazoles from aromatic ketones and benzothiazoles
under I2-free conditions is a challenge. Recently, we developed an
iron-catalyzed arylation of benzoazoles with aromatic aldehydes
using oxygen as oxidant.9 We also developed an efficient proce-
dure for 2-aryl benzothiazole formation from aryl ketones and 2-
aminobenzenethiols under metal- and I2-free conditions using
molecular oxygen as oxidant.10,11 In continuation of our interest
in using iron as catalyst and oxygen as oxidant, herein we report
an iron-catalyzed regioselective acylation of benzothiazoles with
aromatic ketones using molecular oxygen as oxidant (Scheme 1).
We began our study by examining the reaction of benzothiazole
(1a) with acetophenone (2a) in H2O/DMSO by using oxygen
(1 atm) as oxidant at 120 °C. When benzothiazole reacted with
1.5 equiv of acetophenone in the absence of any catalyst, no de-
sired product was obtained as determined by GC and 1H NMR
methods (Table 1, entry 1). Then various iron salts were investi-
gated for this reaction under similar reaction conditions. No prod-
uct was observed when Fe2O3 and ferrocene were used (entries 2
and 3). The use of Fe(NO3)3, FeSO4, and Fe2(SO4)3 all gave the de-
sired product in moderate yield together with observable byprod-
uct 2-phenyl benzothiazole (4a) (entries 5–7). Among the various
iron salts examined, FeCl3Á6H2O was the most effective, and its
use resulted in the formation of 3a in 76% yield (entry 8). The
choice of ligands was crucial for this reaction. The combination
of FeCl3Á6H2O with P(Cy)3HBF4 could further improve the reaction
ketones to form a-ketoamides has also been developed under oxi-
dative reaction condition.6 Very recently, Wu and co-workers
developed various approaches to functionalize sp3 C–H bonds in
aryl methyl ketones promoted by I2.7 They also developed a one-
pot synthesis of 2-acylbenzothiazoles from 2-amino benzenethiols
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
⇑
Corresponding author. Tel.: +86 731 58298601; fax: +86 731 58292251.
E-mail addresses: gjdeng@xtu.edu.cn (S. Liu), gjdeng@xtu.edu.cn (G.-J. Deng).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.050

S. Liu et al. / Tetrahedron Letters 54 (2013) 3838–3841
3839
Table 2
O
S
N
O
S
N
FeCl3⋅6H2O
Reaction of 1a with various aryl ketonesa
FeCl3⋅6H2O
R1
R2
R1
+
C
Ar
O2
Ar
S
N
O
O
S
S
N
P(Cy)3HBF4
+
+
Ar
Ar
R1
Scheme 1. General reaction.
DMSO, H2O
120 °C, O2
N
Ar
1a
2
3
4
yield to 91%, together with 8% of byproduct 4a (entry 14). Solvent
also played an important role in this transformation, the reactions
in other solvents all decreased the reaction yields significantly, and
no desired product was formed in the absence of DMSO (entries
15–19). Much lower yield was obtained when the reaction was car-
ried out under an atmosphere of air (entry 20). The reaction tem-
perature is another important factor for the yield of the product.
Increasing the reaction temperature increased the yield of the
byproduct and decreased the desired product yield (entry 21).
Under the optimized reaction conditions, the scope and gener-
ality of the oxidative condensation were explored (Table 2).12
The reactions with aromatic ketones bearing electron-donating
groups at the aromatic ring proceeded smoothly to give the desired
products in good yields (entries 2 and 3). Functional groups such as
fluoro, chloro, trifluoromethyl, and nitro were well tolerated under
the optimized reaction conditions (entries 4–8). The position of
substituents on the phenyl ring of ketones affected the selectivity
significantly, and the use of 2-chloroacetophenone (2f) afforded
3f and 4f in 80% total yield (entry 6). Notably, the coupling of het-
ero aromatic ketone 2-acetylthiophene (2j) with 1a afforded 3j in
65% yield (entry 10). To our delight, besides aromatic ketones,
other aromatic carbonyl compounds such as propiophenone (2k)
and ethyl benzoylacetate (2l) also reacted with 1a to give the de-
sired products in good yields (entries 11 and 12). Unfortunately,
aliphatic ketones are not suitable substrates for this kind of trans-
formation under the optimal reaction conditions.
Entry
Ketone
Product
Yieldb (%)
O
O
S
N
R
R
1
2
3
4
5
6
R = H
R = 4-Me
R = 4-OMe
R = 4-F
R = 4-Cl
R = 2-Cl
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
75
72
78
81
76
80
3e
3f + 4f
(3:1)
3g
7
8
R = 3-CF3
R = 3-CF3
2g
2h
75
64
3h
O
3i + 4i
(4.3:1)
9
2i
80
O
10
11
12
2j
3j
65
76
81
S
O
3a + 4a
(1.5:1)
2k
2l
Ph
O
O
3a + 4a
(4.4:1)
Ph
OEt
a
Conditions: 1a (0.2 mmol), 2a (0.3 mmol), FeCl3Á6H2O (5 mol %), P(Cy)3HBF4
(5 mol %), DMSO/H2O (0.4 mL, 3:1), 120 °C, 20 h, under oxygen.
b
Isolated yield based on 1a.
Table 1
Optimization of the reaction conditionsa
To further explore the scope of the reaction, various benzothiaz-
oles were employed to react with 2a under the optimized reaction
conditions (Table 3). A series of functional groups including
methyl, methoxy, chloro, bromo, and nitro were well tolerated un-
der the optimal conditions, and the desired products were ob-
tained in moderate to good yields (Table 3, entries 1–7). The
position of the substituents on the phenyl ring of benzothiazoles
affected the reaction yield significantly, and the use of 4-methyl-
benzothiazole (1i) afforded the desired product in 15% yield as de-
tected by GC (entry 8). Under the optimized reaction conditions,
the reaction of 2-aminothiophenol with acetophenone also gave
the desired product 3a in 52% yield which was lower than the reac-
tion yield of benzothiazole with acetophenone (entry 9). Unfortu-
nately, benzoxazoles are not good substrates for this
transformation under the optimized reaction conditions.
O
S
N
S
N
S
O
catalyst
+
+
Ph
120 o
C
Ph
N
Ph
O2
1a
Entry
2a
3a
Solvent
4a
Catalyst
Ligand
Yieldb (%)
3a
4a
1
2
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:2)
H2O/DMSO (1:3)
DMSO
0
0
0
0
0
0
Fe2O3
3
4
Ferrocene
Fe(acac)3
20
42
40
55
75
76
70
77
65
82
91
25
0
5
5
6
Fe2(NO3)3
FeSO4
13
14
16
18
19
14
15
12
12
8
3
0
0
0
0
8
21
7
Fe2(SO4)3
8
9
FeCl2Á4H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
FeCl3Á6H2O
To get more information about the reaction mechanism, several
control experiments were set up under the standard conditions.
We performed a 13C labeling experiment under the optimized con-
10
11
12
13
14
15
16
17
18
19
20c
21d
PPh3
dppm
P(Cy)3
ditions with acetophenone-a-
13C. The corresponding adducts 3a
P(Cy)3HBF4
P(Cy)3HBF4
P(Cy)3HBF4
P(Cy)3HBF4
P(Cy)3HBF4
P(Cy)3HBF4
P(Cy)3HBF4
P(Cy)3HBF4
P(Cy)3HBF4
and 4a with 13C were obtained in 84% total yield (Schemes 1 and
2). The reaction of benzothiazole with phenylglyoxal showed much
poor selectivity and gave 4a as the major product (Scheme 2).
Based on these observations and our previous research,9 a possible
reaction mechanism is described as follows using benzothiazole
(1a) and acetophenone (2a) as an example (Scheme 3). Initially,
benzothiazole 1a was converted to 2-aminothiophenol (A) via
ring-opening reaction in the presence of Lewis acid catalyst
FeCl3Á6H2O,13 which is similar to our previous work with aromatic
aldehydes.9a In the meanwhile, acetophenone 2b was oxidized to
phenylglyoxal (B) which is similar to the I2 promoted sp3 C–H
DMF
Toluene
NMP
H2O
H2O/DMSO
H2O/DMSO
0
0
0
35
65
a
Conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol %), ligand (5 mol %),
solvent (0.4 mL), 120 °C, 20 h, under oxygen.
b
GC yield.
Under air.
140 °C.
c
d

3840
S. Liu et al. / Tetrahedron Letters 54 (2013) 3838–3841
Table 3
SH
S
Reaction of 2a with various benzothiazolesa
FeCl3
N
FeCl3⋅6H2O
P(Cy)3HBF4
NH2
S
N
O
O
S
N
SH
N
Ph
O
1a
A
+
R
R
Ph
DMSO, H2O
120 oC, O2
Ph
O
O
FeCl3
1
2a
3
C
H
Ph
DMSO
O2
Ph
Entry
1
Benzothiazole
Product
Yieldb (%)
70
2b
O
B
S
1b
3k
O
S
N
O
S
O2
H2O
MeO
S
N
N
H
D
Ph
N
3a
Ph
2
3
4
5
6
7
1c
1d
1e
1f
3l
67
72
78
75
76
65
EtO
S
Scheme 3. Proposed mechanism.
3m
3n
3o
3p
3q
N
F
S
N
fords an efficient alternative route for the synthesis of
acylbenzothiazoles under I2-free conditions. The scope, mecha-
nism, and synthetic applications of this reaction are under
investigation.
Cl
S
N
S
Br
Acknowledgments
1g
1h
N
This work was supported by the National Natural Science Foun-
dation of China (21172185), the Hunan Provincial Natural Science
Foundation of China (11JJ1003, 12JJ7002), the New Century Excel-
lent Talents in University from Ministry of Education of China
(NCET-11-0974), and the Scientific Research Foundation for Re-
turned Scholars, Ministry of Education of China (2011-1568).
O2N
S
N
S
N
8c
9
1i
1j
3r
15
52
SH
Supplementary data
3a
NH2
Supplementary data associated with this article can be found, in
a
the
online
version,
at
http://dx.doi.org/10.1016/
Conditions: 1a (0.2 mmol), 2a (0.3 mmol), FeCl3Á6H2O (5 mol %), P(Cy)3HBF4
(5 mol %), DMSO/H2O (0.4 mL, 3:1), 120 °C, 20 h, under oxygen.
j.tetlet.2013.05.050.
b
Isolated yield based on 1a.
GC yield.
c
References and notes
1. (a) Zirngibl, L. Antifungal Azoles: A Comprehensive Survey of their Structures and
Properties; Wiley-VCH: Weinheim, 1998; (b) Katritzky, A. R.; Rees, C. W.;
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functionalization.7c,14 The condensation of A and B generated an
imine intermediate C, which could afford D via intramolecular
cyclization. Finally, the oxidative dehydrogenation of D provided
the desired product 3a.
In summary, we have developed an efficient 2-acylbenzo thia-
zole formation from benzothiazoles and aromatic ketones cata-
lyzed by iron salts under an atmosphere of oxygen. Solvent
played an important role in this transformation and the best yield
was obtained in a mixture of H2O/DMSO. Functional groups such as
methyl, methoxy, fluoro, chloro, bromo, and nitro were all well tol-
erated under the optimized reaction conditions. This method af-
3. (a) Chikashita, H.; Ishibaba, M.; Ori, K.; Itoh, K. Bull. Chem. Soc. Jpn. 1988, 61,
3637; (b) Ishi, H.; Odashima, T.; Kawamonzen, Y.; Katahira, A.; Odashima, T.
FeCl3⋅6H2O
P(Cy)3HBF4
S
N
S
N
O
O
S
N
C 13
C
13 C
C
13Ph
+
(1)
(2)
+
Ph
DMSO, H2O
120 °C, O2
Ph
4a
3a
3a 4a
84% (
:
= 10:1)
FeCl3⋅6H2O
P(Cy)3HBF4
O
S
O
S
N
S
H
+
Ph
+
Ph
DMSO, H2O
120 °C, O2
N
N
Ph
O
78% (3a:4a = 2:3)
Scheme 2. Control experiments.

S. Liu et al. / Tetrahedron Letters 54 (2013) 3838–3841
3841
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0.01 mmol), P(Cy)3HBF4 (3.7 mg, 0.01 mmol), benzothiazole (1a, 21.8 lL,
0.2 mmol), acetophenone (2a, 35 lL, 0.3 mmol), H2O (0.1 mL), and DMSO
(0.3 mL). The reaction vessel was flushed with oxygen and sealed. The resulting
solution was heated to 120 °C for 20 h. After cooling to room temperature, the
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J = 7.6 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.55–7.61 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 185.3, 167.2, 154.0, 137.1, 135.1, 133.9, 131.3, 128.5, 127.6, 126.9,
125.8, 122.2; MS (EI) m/z (%) 239, 211, 105 (100), 77, 51.
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