Efficient and economical access to substituted benzothiazoles: Copper-catalyzed coupling of 2-haloanilides with metal sulfides and subsequent condensation

Full text of DOI:10.1002/anie.200900486

Communications
DOI: 10.1002/anie.200900486
Heterocycles
Efficient and Economical Access to Substituted Benzothiazoles:
Copper-Catalyzed Coupling of 2-Haloanilides with Metal Sulfides and
Subsequent Condensation**
Dawei Ma,* Siwei Xie, Peng Xue, Xiaojing Zhang, Jinhua Dong, and Yongwen Jiang*
Substituted benzothiazoles are one of the most important
classes of heterocycles for pharmaceutical purposes; they
exist in numerous bioactive molecules such as the clinically
used drug zopolrestat (1, for the treatment of diabetes;
Figure 1),[1] selective fatty acid amide hydrolase inhibitor 2,[2]
aldose reductase inhibitor 3,[3] antitumor agents 5F203 (4)[4]
based zinc sensor,[8] a bioluminogenic substrate,[9] some
cleavage agents for soluble oligomers[10] of amyloid
b-peptides, and ligands for catalytic reactions.[11]
The common methods for the assembly of benzothiazoles
are based on the condensation of 2-aminothiophenols with
carboxylic acids or aldehydes,[4,7,11,12] but such methods suffer
from difficulties in the preparation of readily oxidized
2-aminothiophenols. An alternative approach starts from
2-haloanilides,[13] however, in most cases the conversion of the
amides into the corresponding thioamides using P4S10 or
Lawessonꢀs reagent is required, but is generally not feasible
for substrates comprised of ketone, ester, and amide moieties.
To overcome this drawback, Itoh and Mase developed a novel
and practical synthesis of benzothiazoles by using a palla-
dium-catalyzed thiol cross-coupling reaction of 2-haloanilides
and 2-ethylhexyl 3-mercapto-propionate.[14] The disadvantage
of this method lies in the considerable costs for both the
catalyst and the thiol reagent.
In the course of our studies on new methods for hetero-
cycle synthesis through copper-catalyzed coupling reactions
of 2-haloanilides with nucleophiles,[15,16] we attempted to use
some metal sulfides as coupling partners. We were pleased to
find that their coupling with 2-haloanilides worked well to
give benzothiazoles after an acidic workup. To the best of our
knowledge, this is the first successful example for the use of
metal sulfides as coupling partners in a metal-catalyzed
arylation.[17,18] Herein we disclose the details of our results.
As indicated in Table 1, we started our studies by
conducting a CuI/l-proline catalyzed coupling reaction of
N-(2-iodophenyl)-acetamide (7a) with Na2S·9H2O (Table 1,
entry 1). It was found that after 12 hours at 808C, 7a was
completely consumed; the reaction mixture was then treated
Figure 1. Structures of bioactive substituted benzothiazoles.
and PMX 610 (5),[5] as well as fatty acid oxidation inhibitor
(R)-CVT-3501 (6).[6] Additionally, benzothiazole moieties
have been found frequently in other molecules such as a
rariometric fluorescent pH indicator,[7] an iminocoumarin-
Table 1: Screened reaction conditions for formation of benzothiazole
8a.[a]
[*] Prof. Dr. D. Ma, P. Xue, Dr. Y. Jiang
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
Fax: (+86)21-6416-6128
E-mail: madw@mail.sioc.ac.cn
Entry
T [8C]
Acid
Yield [%][b]
jiangyw@mail.sioc.ac.cn
1
2
3
4
5
6
80
80
80
80
60
80
HCl
HCl
HCl
CF3CO2H
–
67[c]
67
S. Xie, Prof. Dr. X. Zhang, J. Dong
Shenyang Pharmaceutical University
103 Wenhua Lu, Shengyang 110016 (China)
83[d]
83[d]
–
[**] The authors are grateful to the Chinese Academy of Sciences and the
National Natural Science Foundation of China (grant 20621062 and
20872156) for their financial support.
HCl
15[d]
[a] Reaction conditions for the coupling step: 7a (1 mmol), Na2S·9H2O
(2 mmol), CuI (0.1 mmol), DMF (2 mL). [b] Yield of isolated product.
[c] 0.2 mmol of l-proline was added. [d] Used 3 mmol of Na2S·9H2O.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900486.
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Table 3: Synthesis of disubstituted benzothiazoles from aryl iodides.[a]
with 12n HCl to afford benzothiazole 8a in 67% yield. A
similar result was obtained in the absence of l-proline
(Table 1, entry 2), indicating that a ligand is not required in
the coupling step. A better yield was obtained by increasing
the amount of Na2S·9H2O to three equivalents (Table 1,
entry 3). Changing the acid to CF3CO2H had no influence on
this process (Table 1, entry 4), and coupling did not occur
when the reaction temperature was lowered to 608C (Table 1,
entry 5). CuI was found to be crucial, as evidenced by the fact
that only 15% of 8a was isolated in the absence of this
catalyst (Table 1, entry 6).
Having the optimized the reaction conditions, we exam-
ined a series of 2-haloanilides to establish the scope and limits
of this process. As summarized in Table 2, by using the
present method, a considerable number of functional groups
could be introduced into the 2-position of the benzothiazoles,
including simple and functionalized alkyl groups (Table 2,
Entry
Product
Yield [%][b]
1
2
3
4
5
6
7
8
8p: X=F
8q: X=Br
75
78
64
8r: X=NO2
8s: X=COCH3
8t: X=CO2H
8u: X=Me
8v: X=OMe
8w: X=NHCOCH3
71[c]
82[d]
81
73
81
9
10
8x: X=OMe
8y: X=F
78
77[c]
12
69
Table 2: Assembly of 2-substituted benzothiazoles from aryl iodides.[a]
4
13
14
15
16
55
8z
8aa
Entry
R
Product
Yield [%][b]
51
1
2
3
4
5
6
7
8
iPr
Bn
8b
8c
8d
8e
8 f
8g
8h
8i
8j
8k
8l
8m
8n
8o
82
72
CH2NHBoc
H
Ph
71[c]
68[c]
90
81[c]
8ab
8ac
4-CF3C6H4
4-NH2C6H4
2-HOC6H4
4-MeOC6H4
4-HOC6H4
4-HO-3-MeOC6H3
2-pyridinyl
2-((1H-indol-3-yl)methyl
2-furanyl
60
68
85
88
87
85
76
9
10
11
12
13
14
[a] Reaction conditions:
7
(1 mmol), Na2S·9H2O (3 mmol), CuI
(0.1 mmol), DMF (2 mL), 808C, 12 h, then added of 0.8 mL of
12n HCl, RT, 5–10 h. [b] Yield of isolated product. [c] K2S was used.
[d] 3-acetamido-4-iodobenzoic methyl ester was employed as the starting
material.
72
74[d]
84[c]
[a] Reaction conditions:
7 (1 mmol), Na2S·9H2O (3 mmol), CuI
(0.1 mmol), DMF (2 mL), 12 h, then added 0.8 mL of 12n HCl, RT, 5–
10 h. [b] Yield of isolated product. [c] K2S was used. [d] Used 0.2 mmol
CuI.
process, as both aryl iodides having electron-withdrawing and
electron-donating groups gave the corresponding products in
good yields (Table 3, entries 1–10). Secondly, several func-
tional groups, such as fluoro, bromo, nitro, ketone, methoxy,
and amido groups, are well-tolerated under these reaction
conditions. These functional groups would allow additional
transformations to give more complex benzothiazoles. In the
case of an ester-substituted aryl iodide, the formation of the
benzothiazole was accompanied by hydrolysis of the ester
moiety, leading to the isolation of acid 8t (Table 3, entry 5).
Thirdly, both 2,5- and 2,6-disubstituted benzothiazoles and a
pyridine-fused benzothiazole (Table 3, entry 16) could be
elaborated from the corresponding aryl iodides. By taking
advantage of this, antitumor agent 5F203 (4) (Table 3,
entry 12),[4] and some known key intermediates for bioactive
molecules, including compounds 8x (Table 3, entry 9; for fatty
acid oxidation inhibitor 6[6]), 8z (Table 3, entry 13; for fatty
acid amide hydrolase inhibitor 2[2]), and 8ab (Table 3,
entry 15; for synthesizing fungicide[22]), were effectively
prepared.
entries 1–3), protons (Table 2, entry 4), substituted aryl
groups (Table 2, entries 5–11), as well as heterocycles
(Table 2, entries 12–14). For the formation of 8d, 8e, and
8o, anhydrous potassium sulfide was employed as the
coupling partner (Table 2, entries 3, 4, and 14). In these
cases, Na2S·9H2O gave low yields of the products because of
the competing amide of amide hydrolysis. Notably, benzo-
thiazole 8h has been reported to have potent tyrosine kinase
inhibition and antitumor activity,[19] whereas compounds 8l–
8n could be used for the assembly of an antitumor agent,[20] an
antiparasitic agent,[21] and an analogue of aldose reductase
inhibitor 3,[3] respectively.
A number of disubstituted benzothiazoles could be
elaborated from trisubstituted aryl iodides (Table 3). The
scope of this process was broad because of the following
aspects: firstly, it seems that the electronic nature of the
additional substituent has little influence on the reaction
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Communications
We next explored the possibility of employing aryl
of the other existing methods for producing substituted
benzothiazoles and in many cases would have definite
advantages in terms of the scope and the conditions of the
reaction. Thus, it can find numerous applications in organic
synthesis. Additionally, the successful application of metal
sulfides as coupling partners will stimulate studies on metal-
catalyzed S-arylation by employing these inexpensive
reagents.
bromides as substrates and found that their reaction with
K2S under our standard conditions is sluggish. However, when
the reaction temperature was raised to 1408C, a satisfactory
conversion was achieved to give benzothiazoles in moderate
to good yields (Table 4). Notably, a 2,4,6-trisubstituted
benzothiazole was obtained in 66% yield from N-(2-bromo-
4,6-dimethylphenyl)acetamide (Table 4, entry 5), thus further
demonstrating the enormous potential of our method for the
assembly of polysubstituted benzothiazoles.
Experimental Section
Typical procedure: A mixture of CuI (19 mg, 0.1 mmol), o-iodoben-
zamide (1 mmol), and Na2S·9H2O (or K2S) (3 mmol) in DMF (2 mL)
was stirred at 808C for 12 h. The reaction mixture was cooled to RT
and then 0.8 mL of conc. HCl was added and the reaction mixture
stirred for 5–10 h. After adding 10 mL saturated aq. NaHCO3, it was
extracted with ethyl acetate and then purified by silica gel chroma-
tography to furnish the desired product.
Table 4: Assembly of substituted benzothiazoles from aryl bromides.[a]
Entry
R
X (for 8)
Product
Yield [%][b]
1
2
3
4
5
6
Ph
H
H
8 f
88
78
66
41
86
63
4-NH2-3-MeC6H3
Me
Me
Ph
8ad
8ae
8x
8af
8m
Received: January 26, 2009
Published online: May 7, 2009
4,6-dimethyl
5-methoxy
6-fluoro
H
Keywords: biological activity · catalysis · cross-coupling ·
.
2-pyridinyl
heterocycles · sulfur
[a] Reaction conditions: 9 (1 mmol), K2S (3 mmol), CuI (0.1 mmol),
DMF (2 mL), 1408C, 12 h, then added 0.8 mL of 12n HCl, RT, 5–10 h.
[b] Yield of isolated product.
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Angew. Chem. Int. Ed. 2009, 48, 4222 –4225
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