Synthesis of 2-Acylbenzothiazoles via the Cu(OTf)2-Catalyzed tandem reaction of β,β-Dihalidestyrenes with 2,2′- Disulfanediyldianilines

Article abstract of DOI:10.1055/s-0033-1340288

A new method has been developed for the one-pot construction of 2-acylbenzothiazoles via the Cu(OTf)₂-catalyzed tandem reaction of β,β-dihalidestyrenes with 2,2′-disulfane-diyldianilines. A variety of different dihalidestyrenes and diphenyldisulfanes were efficiently converted into the corresponding 2-acylbenzothiszole derivatives in the presence of Cu(OTf)₂. Most importantly, this protocol allowed for the long chain 1,1-dibromohept-1-ene to be converted into the corresponding 2-hexylbenzo[d]thiazole in moderate yield. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340288

LETTER
▌255
lSetyternthesis of 2-Acylbenzothiazoles via the Cu(OTf)2-Catalyzed Tandem Reac-
tion of β,β-Dihalidestyrenes with 2,2′-Disulfanediyldianilines
Synthesis of 2-Acylbenzothiazoles
Zeng-Le Zhou, Tao Fang, Ri-Yuan Tang, Xing-Guo Zhang, Chen-Liang Deng*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(577)86689300; E-mail: dengchenliang78@tom.com
Received: 21.08.2013; Accepted after revision: 17.10.2013
palladium-catalyzed coupling of aryl halides with organo-
Abstract: A new method has been developed for the one-pot con-
metallic agents,8 and the condensation reactions of 2-ami-
struction of 2-acylbenzothiazoles via the Cu(OTf)2-catalyzed tan-
nothiophenol with alkynyl bromides,9 methyl ketones,10
dem reaction of β,β-dihalidestyrenes with 2,2′-disulfane-
diyldianilines. A variety of different dihalidestyrenes and diphenyl-
and dihalidestyrene.11 Although these methods provide
disulfanes were efficiently converted into the corresponding 2-acyl- efficient access to the desired 2-acylbenzothiazoles, they
benzothiszole derivatives in the presence of Cu(OTf)2. Most
importantly, this protocol allowed for the long chain 1,1-dibromo-
hept-1-ene to be converted into the corresponding 2-hexylben-
conditions. The development of a mild, environmentally
zo[d]thiazole in moderate yield.
generally require expensive catalysts, specially made
starting materials, hazardous reagents or harsh reaction
benign and efficient method is therefore highly desirable.
To the best of our knowledge, there have been no reports
in the literature to date describing the synthesis of 2-acyl-
Keywords: Cu(OTf)2, dihalidestyrene, diphenyldisulfane, 2-acyl-
benzothiazole, tandem reaction
benzothiazoles via the Cu(OTf)2-catalyzed tandem reac-
tion of dihalidestyrenes with diphenyldisulfane.12 Herein,
Benzothiazoles are an important class of heterocyclic
we report our studies of Cu(OTf)2-catalyzed tandem reac-
compounds,1 and examples belonging to this class can be
found in a large number of natural products. Moreover,
tion of β,β-dihalidestyrenes with 2,2′-disulfanediyldiani-
lines for the synthesis of 2-acylbenzothiazoles under mild
they are used as building blocks for the construction of
conditions (Scheme 1).
pharmaceutical agents.2 A large number of compounds
The reaction between β,β-dibromo-4-methoxystyrene
(1a) and 2,2′-disulfanediyldianiline (2a) was selected as a
model reaction to optimize the reaction conditions for the
containing the benzothiazole moiety have been reported
in the literature to exhibit potent biological activities
against a number of different targets of medicinal signifi-
transformation, and the results are shown in Table 1. The
cance,3 and 2-substituted benzothiazoles, in particular,
reaction of 1a with 2a was initially conducted in the pres-
ence of CuI (10 mol%) using Cs2CO3 (2 equiv) as a base
have been shown to exhibit remarkable levels of biologi-
cal and therapeutically relevant activity, which have at-
and DMSO (2 mL) as a solvent. This reaction gave the de-
tracted considerable interest from researchers working in
sired product 3 in 45% yield (Table 1, entry 1). When the
reaction was conducted in the absence of base, none of the
the pharmaceutical sciences.4 For example, RWJ-56423,
which contains a benzothiazole 2-ketone structure, has
target product was observed by GC–MS (Table 1, entry
been reported as a therapeutic agent for the treatment of
2), demonstrating that the base plays a critical role in the
allergic and inflammatory disorders.5 Although a variety
reaction. Encouraged by this result, we proceeded to in-
of different methods have been reported to date for the
vestigate the effects of a series of different bases on the
synthesis of 2-arylbenzothiazole derivatives, reports per-
outcome of the model reaction, including CsOAc, K2CO3,
taining to the synthesis of 2-acylbenzothiazoles have been
and t-BuONa (Table 1, entries 3–5). The results of these
experiments revealed that strong bases gave better yields
scarce because of the difficulties associated with introduc-
ing an acyl group at the 2-position of benzothiazoles.6
than weaker bases, with Cs2CO3 providing the best result.
Only a few methods have been reported in the literature
Having identified the best base for the reaction, we pro-
for the formation of 2-acylbenzothiazoles, including the
ceeded to investigate a number of different solvents, in-
condensation of acyl chloride with organometallics,7
H2N
O
S
N
Cu(OTf)2 (10 mol%)
Cs2CO3 (2 equiv)
S
R2
Br/Cl
Br/Cl
R1
S
R2
+
R1
DMSO (2 mL)
120 °C, 20 h, air
NH2
R2
Scheme 1 Cu(OTf)2-catalyzed tandem reaction and synthesis of 2-acylbenzothiazoles
SYNLETT 2014, 25, 0255–0260
Advanced online publication: 03.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340288; Art ID: ST-2013-W0804-L
© Georg Thieme Verlag Stuttgart · New York

256
Z.-L. Zhou et al.
LETTER
cluding toluene, MeCN, DMF, THF and dioxane, With the optimized reaction conditions in hand, we pro-
although all of these solvents were inferior to DMSO in ceeded to explore the scope of the reaction in terms of sub-
terms of the yield (Table 1, entries 6–10). We also inves- strates 1 and 2, and the results are summarized in Table 2.
tigated the effects of a series of cuprous and cupric salts, Generally, substrates 1a–g, which contained electron-do-
including CuI, CuBr, Cu(OAc)2, Cu(OTf)2, and CuBr2. nating or electron-withdrawing groups, were well tolerat-
The results of these screening experiments revealed that ed under the optimal conditions with the desired products
all of the copper salts investigated enhanced the reactivity obtained in moderate to good yields (Table 2, entries 1–6).
of the reaction, with Cu(OTf)2 being the most efficient of For example, substrate 1b reacted smoothly with 2a to
all of the copper additives tested in this regard. For exam- give the desired product in 68% yield (Table 2, entry 1).
ple, the use of CuBr, Cu(OAc)2, Cu(OTf)2 and CuBr2 in Substrates 1c and 1d, bearing electron-donating groups
the reaction afforded the target product in 17%, 34%, 53% (i.e., Me and NMe2, respectively) on their aromatic rings,
and 31% yields, respectively (Table 1, entries 11–14). Fi- also reacted successfully with 2a under the optimized re-
nally, the reaction temperature was also investigated. action conditions, although the corresponding products 5
Pleasingly, an increase in the reaction temperature to and 6 were formed in lower yields (Table 2, entries 2 and
100 °C led to a significant increase in the yield of the de- 3). Substrates 1e–g, bearing electron-withdrawing groups
sired product 3 to 71% (Table 1, entry 15). Further in- (i.e., NO2, CN and F, respectively), were also compatible
creasing the reaction temperature to 120 °C led to the best with the optimized conditions, and afforded the corre-
yield for the reaction (Table 1, entry 16), whereas increas- sponding products in moderate yields (Table 2, entries 4–
ing the temperature to 130 °C led to a decrease in the yield 6). Substrates 1h–k, which were substituted with bulky
(Table 1, entry 17).
functional groups at the 2-position of their aromatic rings,
Table 1 Optimized Reaction Conditionsa
H2N
O
S
N
MeO
S
Br
[Cu] (10 mol%)
S
+
Br
NH2
1a
2a
OMe
3
Entry
[Cu] (10 mol%)
Base (2 equiv)
Solvent (2 mL)
Temp (°C)
Yield (%)b
1
2
CuI
Cs2CO3
–
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
MeCN
DMF
80
80
45
–
CuI
3
CuI
CsOAc
K2CO3
t-BuONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
80
<10
20
4
CuI
80
5
CuI
80
39
6
CuI
80
trace
20
7
CuI
80
8
CuI
80
32
9
CuI
THF
80
trace
trace
17
10
11
12
13
14
15
16
17
CuI
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
80
CuBr
Cu(OAc)2
Cu(OTf)2
CuBr2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
80
80
34
80
53
80
31
100
120
130
71
86
73
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Cu] (10 mol%), DMSO (2 mL), stirring at 120 °C for 20 h under air.
b Isolated yield.
Synlett 2014, 25, 255–260
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Acylbenzothiazoles
257
were well tolerated under the optimized reaction condi- group on their aromatic ring, also reacted efficiently with
tions and gave the desired products in 38–56% yields (Ta- 1a to afford the corresponding substituted benzothiazoles
ble 2, entries 7–10). Substrate 1k, for instance, contained in 65% and 62% yields, respectively (Table 2, entries 16
a bulky CN group on its aromatic ring, and reacted and 17). Surprisingly, substituted β,β-dichlorostyrenes,
smoothly with 2a to give the corresponding 2-acylbenzo- which are less active than the corresponding bromo-sub-
thiazole product 13 in 48% yield (Table 2, entry 10). The stituted compounds, were also found to be suitable sub-
meta-substituted substrates 1l and 1m also reacted suc- strates for the reaction, and afforded the target products in
cessfully under the optimized conditions to afford the de- moderate to good yields, albeit following a longer reac-
sired products 14 and 15 in 64% and 61% yields, tion time (Table 2, entries 18–20). For example, the reac-
respectively (Table 2, entries 11 and 12). The optimized tion of the dichlorostyrene substrate 1q with 2a proceeded
reaction conditions were also tolerant of heterocyclic sub- smoothly under the optimized conditions to give the target
strates such as 1n and 1o, which gave the corresponding product 3 in 81% yield (Table 2, entry 18). The β,β-di-
cyclization products in 52% and 56% yields, respectively chlorostyrene 1r reacted efficiently with 2a to give the cy-
(Table 2, entries 13 and 14). It is noteworthy that the long- clized product in 64% yield (Table 2, entry 19). Substrate
chain alkyl substrate 1p converted into the product 18 in 1s, bearing an electron-withdrawing NO2 group at the
50% yield under the optimal conditions (Table 2, entry para-position of its aromatic ring, reacted successfully
15). The scope of 2,2′-disulfanediyldianilines 2 was also with 2a to give the 2-acylbenzothiazole 8 in 55% yield
examined. Substrates 2b and 2c bearing a Cl and a Me (Table 2, entry 20).
Table 2 Cu(OTf)2-Catalyzed Tandem Reaction of β,β-Dihalidestyrenes with 2,2′-Disulfanediyldianilinesa
H2N
O
S
N
Cu(OTf)2 (10 mol%)
Cs2CO3 (2 equiv)
S
R2
X
R1
S
R2
+
R1
DMSO (2 mL)
120 °C, 20 h, air
X
NH2
R2
1
2
4–20
X = Br, Cl
Entry
1
2
Products
Yield (%)b
Br
1
1b
1c
2a
4
S
N
68
Br
Br
O
O
2
3
2a
2a
5
6
31
30
S
N
Br
NMe2
Me2N
Br
1d
1e
1f
S
N
Br
O
O
O
CN
NC
Br
4
5
2a
2a
7
8
53
57
S
N
Br
NO2
O2N
Br
S
N
Br
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 255–260

258
Z.-L. Zhou et al.
LETTER
Table 2 Cu(OTf)2-Catalyzed Tandem Reaction of β,β-Dihalidestyrenes with 2,2′-Disulfanediyldianilinesa (continued)
H2N
O
S
N
Cu(OTf)2 (10 mol%)
Cs2CO3 (2 equiv)
S
R2
X
R1
S
R2
+
R1
DMSO (2 mL)
120 °C, 20 h, air
X
NH2
R2
1
2
4–20
X = Br, Cl
Entry
1
2
Products
Yield (%)b
F
F
Br
6
1g
2a
9
52
S
N
Br
O
O
O
O
O
O
O
Br
Br
S
N
7
8
1h
1i
2a
2a
2a
2a
2a
2a
2a
10
11
12
13
14
15
16
39
56
38
48
64
61
52
Br
Br
OMe
OMe
Br
F
S
N
Br
Br
Br
S
N
9
1j
F
Br
Br
10c
11
12
13
1k
1l
S
N
CN
CN
OMe
Br
S
N
MeO
Br
Cl
Br
S
N
1m
1n
Cl
Br
Br
S
Br
S
S
N
O
Br
O
Br
Br
O
S
14
15
1o
1p
2a
2a
17
18
56
50
N
S
O
C5H11
C5H11
Br
N
OMe
H2N
Cl
S
16
1a
2b
19
65
S
S
N
Cl
NH2
O
Cl
Synlett 2014, 25, 255–260
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Acylbenzothiazoles
259
Table 2 Cu(OTf)2-Catalyzed Tandem Reaction of β,β-Dihalidestyrenes with 2,2′-Disulfanediyldianilinesa (continued)
H2N
O
S
N
Cu(OTf)2 (10 mol%)
Cs2CO3 (2 equiv)
S
R2
X
R1
S
R2
+
R1
DMSO (2 mL)
120 °C, 20 h, air
X
NH2
R2
1
2
4–20
X = Br, Cl
Entry
1
2
Products
Yield (%)b
OMe
H2N
S
17
1a
2c
20
62
S
S
N
NH2
O
MeO
Cl
18c
19c
20c
1q
1r
1s
2a
2a
2a
3
4
8
81
64
55
Cl
Cl
Cl
O2N
Cl
Cl
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Cu(OTf)2 (10 mol%), Cs2CO3 (2 equiv), DMSO (2 mL) reacted at 120 °C under air until
complete consumption of the starting material monitored by TLC and GC–MS.
b Isolated yield.
c Reaction time was 36–48 h.
Based on our own results, as well as information from the derivatives via the reaction of β,β-dihalidestyrenes with
literatures,6c,g,9,13 we have proposed a possible mechanism 2,2′-disulfanediyldianilines. It is noteworthy that the pro-
for the current transformation, which is shown in Scheme tocol allowed for the long-chain 1,1-dibromohept-1-ene
2. The initial reaction of substrate 1a with base would to be converted into 2-hexylbenzo[d]thiazole in moderate
yield intermediate A, which would undergo a condensa- yield. Further studies aimed at expanding the scope of this
tion reaction with 2a to give intermediate B, followed by reaction are currently underway in our lab.
an intramolecular cyclization to afford C2. The Cu(II) cat-
alyst would then oxidize intermediate C2 to give the tar-
get product 3 together with the Cu(I) species. The Cu(I)
Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
21102104, 21002070), the Department of Education of the Zhejiang
Province Fund (Nos. 201120337), and Wenzhou University for
their financial support.
species would then be oxidized by air to regenerate the
Cu(II) catalyst to complete the catalytic cycle.
In summary, we have developed a Cu(OTf)2-catalyzed
tandem reaction for the synthesis of 2-acylbenzothiazoles
S
S
NH2
NH2
••
Anisole
Cs2CO3
Br
NH2
2a
Anisole
A
Br
Br
S
Anisole
air
1a
B
Cu(II)
N
Cu(I)
H
N
Anisole
Anisole
Anisole
O
N
S
S
S
3
C2
C1
Scheme 2 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 255–260

260
Z.-L. Zhou et al.
LETTER
1598. (c) Fan, X. S.; He, Y.; Zhang, X. Y.; Guo, S. H.;
Wang, Y. Y. Tetrahedron 2011, 67, 6369. (d) Mu, X. J.;
Zou, J. P.; Zeng, R. S.; Wu, J. C. Tetrahedron Lett. 2005, 46,
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Lett. 2012, 14, 4414. (f) Yang, Z. Y.; Chen, X.; Wang, S. Z.;
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899.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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(13) To a Schlenk tube were added a mixture of β,β-dibromo-
styrene 1a (0.2 mmol) and 2,2′-disulfanediyldianiline 2a
(0.4 mmol), Cu(OTf)2 (10 mol%), Cs2CO3 (2 equiv), and
DMSO (2 mL). Then the mixture was stirred at 120 °C for
the indicated time until complete consumption of starting
material as monitored by TLC and GC–MS analysis. After
the reaction was finished, the mixture was washed with
brine. The aqueous phase was re-extracted with Et2O. The
combined organic extracts were dried over Na2SO4 and
concentrated under vacuum, and the resulting residue was
purified by silica gel column chromatography (hexane–
EtOAc) to afford the target product 3.
Benzo[d]thiazol-2-yl(4-methoxyphenyl)methanone (3):
white solid; mp 120–122 °C. 1H NMR (500 MHz, CDCl3): δ
= 8.58 (d, J = 9.0 Hz, 2 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.94 (d,
J = 8.0 Hz, 1 H), 7.47–7.51 (m, 2 H), 6.98 (d, J = 9.0 Hz, 2
H), 3.85 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 183.4,
167.9, 164.4, 153.9, 136.9, 133.8, 127.8, 127.4, 126.8,
125.5, 122.1, 113.9, 55.6. LRMS (EI, 70 eV): m/z (%) = 269
(21) [M+], 241 (13), 135 (100), 107 (13), 92 (16), 77 (23).
Synlett 2014, 25, 255–260
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