I2 promoted domino oxidative cyclization for one-pot synthesis of 2-acylbenzothiazoles via metal-free sp3 C-H functionalization

Article abstract of DOI:10.1039/c2cc34561g

An I₂ promoted domino protocol was developed to construct 2-acylbenzothiazoles from simple and readily available aromatic ketones/unsaturated methyl ketones and o-aminobenzenethiols. The reaction proceeded smoothly under metal-free and peroxide

Full text of DOI:10.1039/c2cc34561g

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I2 promoted domino oxidative cyclization for one-pot synthesis of
2-acylbenzothiazoles via metal-free sp3 C–H functionalizationw
Yan-Ping Zhu, Mi Lian, Feng-Cheng Jia, Mei-Cai Liu, Jing-Jing Yuan, Qing-He Gao and
An-Xin Wu*
Received 26th June 2012, Accepted 19th July 2012
DOI: 10.1039/c2cc34561g
An I2 promoted domino protocol was developed to construct
2-acylbenzothiazoles from simple and readily available aromatic
ketones/unsaturated methyl ketones and o-aminobenzenethiols.
The reaction proceeded smoothly under metal-free and peroxide-
free conditions.
(2a, 1 mmol) were heated at 80 1C in the presence of I2/CuO
(1.1 mmol/1.1 mmol), the desired product could only be
obtained in a low yield (Table 1, entry 1). The temperature
was subsequently investigated (Table 1, entries 1–3), where
100 1C was found to be the most effective temperature, giving
a moderate result (Table 1, entry 3). Upon increasing the dose
of I2 to 2.0 mmol, the yield was slightly increased (Table 1,
entry 5). However, surprising results were obtained in the
control experiments in which the desired product was observed
in good yield in the absence of metal catalyst CuO (Table 1,
entry 6). The reaction wholly failed perform in the absence
of I2, or I2/CuO (Table 1, entries 7–8). These results suggested
that I2 played a crucial role in the transformation. Various
solvents were also investigated (see ESIw); DMSO was found
to be the most efficient media for the process. After several
experimental iterations, the optimal reaction conditions
emerged with acetophenone 1a (1.0 mmol), 2-aminobenzen-
ethiol 2a (1.2 mmol), and I2 (1.50 mmol) at 100 1C in DMSO
(Table 1, entry 14).
In recent years, catalytic C–H functionalization, especially
an sp3 C–H bond, has drawn considerable interest.1 Many
excellent results have been achieved based on the transition-
metal-catalyzed approach. Very recently, iodide catalyzed
C–H bond functionalization has been established. For example,
the process of quaternary ammonium iodide and TBHP
catalyzing C–H activation to construct C–O, C–N bonds and
heterocycles was well demonstrated by Ishihara,2 Nachtsheim,3
Yu and Han,4 Wan,5 and Zhu.6 I2 and TBHP promoted
functionalization of a C–H bond was also proposed and
utilized by Wang,7 Jiang,8 Prabhu,9 and Wang.10 To further
study iodide catalyzed direct C–H bond functionalization
further methods are still desirable.
Benzothiazole is an important class of heterocycle, which
exists widely in natural products. Many compounds containing
a benzothiazole motif exhibit potent biological activities and
medicinal significance.11 Although the synthesis of 2-arylbenz-
athiazoles has received much interest, 2-acylbenzathiazoles are
rarely synthesized 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-acylbenzathiazoles
thus far.12 Herein, we reported a metal-free and peroxide-free
I2 promoted sp3 C–H bond functionalization protocol to
construct 2-acylbenzothiazoles and their derivatives.
Table 1 Optimization of the reaction conditionsa
Entry I2 (mmol) CuO (mmol) Temp (1C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
1.1
1.1
1.1
1.5
2.0
2.0
—
1.1
1.1
1.1
1.1
1.1
—
1.1
—
—
—
80
90
2.0
2.0
1.5
1.5
1.5
1.0
12
50
53
62
72
75
80
n.r.
n.r.
83
100
100
100
100
100
100
100
110
100
100
100
100
To initiate our study, we optimized the reaction conditions
for the formation of 2-acylbenzothiazole with acetophenone
(1a) and 2-aminobenzenethiol (2a) as substrates (Table 1).
When acetophenone (1a,
1 mmol), 2-aminobenzenethiol
—
12
9
2.0
2.0
0.8
1.0
1.2
1.5
1.0
1.0
2.5
2.0
1.5
1.0
10
11
12
13
14
60
65
Key Laboratory of Pesticide and Chemical Biology,
Ministry of Education, College of Chemistry,
Central China Normal University, 152 Luoyu Road, Wuhan, 430079,
P. R. China. E-mail: chwuax@mail.ccnu.edu.cn;
Fax: +86 027 6786 7773; Tel: +86 027 6786 7773
w Electronic supplementary information (ESI) available: Experi-
mental section, characterization of all compounds, copies of 1H and
13C NMR spectra for isolated compounds. See DOI: 10.1039/
c2cc34561g
—
—
—
—
75
78
82 (86)c
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol) in 3 mL DMSO.
c
= no reaction. Reaction conditions: 1a
b
Isolated yields. n.r.
(1.0 mmol), 2a (1.2 mmol), in 3 mL DMSO.
c
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Table 2 The scope of aryl methyl ketones and o-aminobenzenethiolsa
Table
3 The scope of unsaturated aryl methyl ketones and
o-aminobenzenethiolsa
Reaction conditions: 4 (1.0 mmol), 2 (1.2 mmol), I2 (1.5 mmol) in
DMSO (3 mL) at 100 1C for 1–2.5 h.a Isolated yield.
increase the yields (5b–5d, 5g–5h), while an NO2 group
decreased the yields (5e and 5i). The steric nature of the
unsaturated methyl ketones had little influence on the reaction
efficiency, and all the desired products were obtained in
moderate to good yields (48–72%; Table 3). In addition,
aliphatic ketones, such as acetone, cyclohexanone, and methyl-
ethylketone, were also investigated. However, none of the
desired products were observed under the standard conditions.
The reaction process of 1a (0.1 mmol), 2a (0.12 mmol) with
I2 (0.12 mmol) was monitored by 1H NMR spectroscopy. The
experiment clearly illustrated that the reaction had a good
conversion and yield. The consumption of 1a was very fast at
the first 15 mins (Fig. 1), and the formation of product 3a
was directly related to the consumption of 1a (the integrals
changed at d = 2.57, 8.28, and 8.45 ppm). Moreover, we were
delighted to find that a new species appeared at peak of
5.70–5.80 ppm, which was assigned to the byproduct HI of
Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), I2 (1.5 mmol) in
b
DMSO (3 mL) at 100 1C for 1–2.5 h.a Isolated yield. 1o (1.0 mmol),
2a (1.2 mmol), I2 (1.5 mmol) in DMSO (3 mL) at 80 1C for 2.5 h.
With the optimal conditions in hand, the scope of the
present transformation was investigated with I2 as promoter.
To our satisfaction, the reaction showed a wide scope for
the structure of aromatic methyl ketones (Table 2). Both
electron-donating and electron-withdrawing groups at the
ortho-, meta- or para-position of the phenyl group of 1 could
afford the corresponding products with moderate to good
yields (3a–3i). It should be noted that an electron-donating
substituent on the benzene ring caused a slight increase in
yields. The substrate with a sensitive hydroxy group (OH) on
the phenyl ring presented a moderate 55% yield of 3j, whereas
1-naphthyl methyl ketone (1k) and 2-naphthyl methyl
ketone (1l) afforded satisfying results (80% and 82% yields).
Heteroaryl methyl ketones were also investigated. Hetero-
cycles, including furanyl (1n), thiophenyl (1o, 1p), N-methyl
pyrrolyl (1q), benzofuryl (1r), 3-indolyl (1s) and morpholinyl
(1t), were shown not to affect the overall efficiency, and the
corresponding products 3n–3t were obtained in moderate to
good yields (63–78%). We were pleased to find 2-amino-4-
chlorobenzenethiol (2b) was also tolerant to the reaction.
The corresponding products 3u–3x were thus obtained in
61–83% yields. Agreeably, dual substituted aromatic methyl
ketone 1,10-(1,3-phenylene)diethanone (1y) could also afford
the corresponding product 3y in 65% yield.
1
inner salt HI-3a via the H NMR titration experiments of 3a
with HI (see ESIw).
To further probe the reaction process, we monitored the
1
reaction of 1a (0.1 mmol) with I2 (0.12 mmol) by H NMR
spectroscopic studies (Fig. 2). Through comparison with
an authentic sample (see ESIw), the signal at 4.6 ppm was
To further expand the scope of the ketones, unsaturated
methyl ketones such as 4a–4e were investigated. To our
delight, unsaturated methyl ketones could also smoothly react
with o-aminobenzenethiols 2 in the presence of I2 to afford the
corresponding products (Table 3). Electron donating groups
attached to the aryl rings, such as MeO, benzyloxy, could
Fig. 1 The reaction process of 1a (0.1 mmol) with 2a (0.12 mmol) in
1
the presence of I2 (0.12 mmol) at 100 1C was monitored by H NMR
spectroscopy (600 MHz, DMSO-d6, 298 +/ꢀ0.5 K).
c
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heterocyclization). In addition, the protocol could provide a
simple, efficient method to synthesize 2-acylbenzathiazoles, in
which a metal, base, and ligand are needless. Further studies
on the applications of this strategy will be reported in due
course.
We thank the National Natural Science Foundation of
China (Grant 21032001) and PCSIRT (No. IRT0953).
Notes and references
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Fig. 2 The reaction process of 1a (0.1 mmol) with I2 (0.12 mmol) was
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Scheme 1 The plausible mechanism of the present reaction.
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assigned to the –CH2– group of a-iodo aryl methyl ketone 1aa
at 2–10 mins (Fig. 2). In addition, the signals at 9.55 ppm
and 5.70 ppm were assigned to the phenylglyoxal aldehyde
group (1ac) and the hemiacetal group (1ab). With the
consumption of 1a, the intermediate 1ab and 1ac appeared
and the concentration subsequently increased over time.
Cocconcelli et al. had previously investigated the assignment
and equilibrium between the aldehyde forms of phenylglyoxal
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1
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These results disclosed that phenacyl iodine (1aa) and
phenylglyoxal (1ac) were important intermediates in the whole
transformation.
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A possible reaction mechanism is described as follows
using acetophenone (1a) and 2-aminobenzenethiol (2a) as an
example (Scheme 1). Initially, the acetophenone 1a was
converted to 1aa in the media of I2.14 Subsequently, it further
converted into phenylglyoxal (1ac) in the presence of
DMSO.15 Finally, phenylglyoxal (1ac) reacted with 2a via
condensation, Michael addition and oxidative dehydrogenation
sequences to afford the desired product 3a in the presence of the
excess or regenerated iodide.16 In the process, byproduct HI
could be oxidized by DMSO to regenerate at least 0.5 equiv of
iodine (eqn (1)).17
In conclusion, an I2 promoted domino protocol has been
developed to construct 2-acylbenzothiazoles from simple
and readily available aromatic ketones/unsaturated methyl
ketones and o-aminobenzenethiols. Mechanistic investigation
disclosed that the transformation contained three mechanistically-
different reactions (iodination, Kornblum oxidation, and
16 M. Ishihara and H. Togo, Synlett, 2006, 2, 227.
17 M. Gao, Y. Yang, Y. D. Wu, C. Deng, W. M. Shu, D. X.
Zhang, L. P. Cao, N. F. She and A. X. Wu, Org. Lett., 2010,
12, 4026.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.