Copper(II)-Promoted Cascade Synthesis of 2-Aminobenzothiazoles Starting from 2-Iodoanilines and Sodium Dithiocarbamates

Article abstract of DOI:10.1002/ejoc.201801122

A facile and efficient formation of 2-aminobenzothiazoles by a copper(II)-promoted one-pot cascade process was developed. The desired 2-aminobenzothiazoles were synthesized in good to excellent yields (up to 97 %) in the presence of Cu(OAc)₂ an

Full text of DOI:10.1002/ejoc.201801122

A Journal of
Accepted Article
Title: Copper(II)-Promoted Cascade Synthesis of 2-
Aminobenzothiazoles Starting from 2-Iodoanilines and Sodium
Dithiocarbamates
Authors: Hui Zhu, Shi-Bo Zhang, Xing Liu, Yu Cheng, Han-Ying Peng,
and Zhi-Bing Dong
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801122
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801122
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European Journal of Organic Chemistry
10.1002/ejoc.201801122
FULL PAPER
Copper(II)-Promoted
Cascade
Synthesis
of
2-
Aminobenzothiazoles Starting from 2-Iodoanilines and Sodium
Dithiocarbamates
[
a]
[a]
[a]
[a]
[a]
[a, b]
Hui Zhu , Shi-Bo Zhang , Xing Liu , Yu Cheng , Han-Ying Peng , Zhi-Bing Dong*
Dedication ((optional))
Abstract: A facile and efficient formation of 2-aminobenzothiazoles
by a copper(II)-promoted one-pot cascade process was developed.
The desired 2-aminobenzothiazoles were synthesized in good to
isothiocyanates
followed
by
oxidative
cyclization
of
thiobenzanilides including Jacobsen’s and Hugerschoff’s
methods (path A, Scheme 2), coupling of benzylamines with
preformed 2-halobenzothiazoles (path B, Scheme 2), Pd or
Cu catalyzed intramolecular heteroarylation of 2-
[
7]
[
8]
excellent yields (up to 97%) in the presence of Cu(OAc)
2
and K
2 3
CO ,
a variety of functional groups on 2-iodoanilines could be tolerated.
The method features ligand-free, mild reaction conditions and good
yields, illustrating its practical synthetic value in some potentially
biologically active compounds.
[
9]
halobenzothioureas (path C, Scheme 2), some metal-free
approaches for the synthesis of 2-aminobenzthiazole have also
been reported recently at high temperature (path C, Scheme
[
10]
2),
the intermediates generated by 2-aminothiophenols with
[
11]
isothiocyanates (path D, Scheme 2).
Introduction
Benzothiazoles, particularly 2-aminobenzothiazoles have
frequently been used as core structures for the development of
[
1]
pharmaceutical agents and they are important intermediates
[2]
and broadly found in biological chemistry and medicinal areas.
Almost all sorts of pharmacophores possessing this construction
units have shown great potential in the development of novel
[3]
therapeutics, for instance, the anti-inflammatory drug (1), the
[
4]
[5]
antibacterial compound (2), the anti-HIV agent (3) and the
[
6]
treatment of amyotrophic lateral sclerosis (4) (Scheme 1).
Scheme 2. Available literature methods for the preparation of 2-
aminobenzothiazoles.
Despite the numerous efforts toward the synthesis of 2-
aminobenzothiazoles, however, the reported methods often
employ expensive metal catalysts, ligands, and multistep
reactions or the prefunctionalization of starting materials which
limit their synthetic applications. To overcome these drawbacks,
the development of a concise route using both commercially
available materials and inexpensive catalytic system remain a
challenging area for exploration. In recent years, copper
catalysts have been successfully applied to the synthesis of
[12]
various heterocyclic compounds through one-pot strategies.
As a part of our efforts towards the development of expeditious
metal-catalyzed diverse methodologies for the synthesis of
biologically active heterocycles, herein we would like to report
Scheme 1. Structures of bioactive 2-N-substituted benzothiazoles.
[13]
The potential of the 2-aminobenzothiazoles has led to them
being encountered through the development of various synthetic
protocols. The classical methodologies employed for their
synthesis involve the condensation of substituted anilines with
our recent efforts towards the synthesis of diverse N-substituted-
2-aminobenzothiazoles promoted by copper(II) salt under ligand-
free conditions (Scheme 3).
[
[
a]
School of Chemistry and Environmental Engineering, Wuhan
Institute of Technology, Wuhan 430205, China.
E-mail: dzb04982@wit.edu.cn
http://cee.wit.edu.cn/info/1052/1538.htm
Department of Chemistry, Ludwig-Maximilians-Universität,
Butenandtstrasse 5-13, 81377 München, Germany.
b]
Scheme 3. Copper-promoted cascade cyclization reaction: the synthesis of 2-
aminobenzothiazoles (this work).
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
10.1002/ejoc.201801122
FULL PAPER
Results and Discussion
equiv.)
equiv.)
1
1
1
4
5
6
Cu(OAc)
2
(1.0
-
DMF
DMF
DMF
DMF
120
130
100
80
22
85
81
48
36
25
71
22
80
90
69
equiv.)
At the outset of the studies, 4-chloro-2-iodoaniline (1) and
sodium dimethyldithiocarbamate (2) were selected as the model
substrates (Table 1). The reaction was initially studied by using
Cu(OAc)
2
(1.0
K
K
K
K
K
K
K
K
K
2
CO
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
K CO (1.0
3
(2.0
equiv.)
Cu(OAc)
2
(1.0
2
3
CuI (10 mol%) as catalyst and Cs
2
CO
3
(2.0 equiv) as base in
equiv.)
DMF at 120°C. To our delight, the desired product 3d could be
isolated with 52% yield (Table 1, entry 1). To further optimize
the reaction, we examined the use of desulfurizing agents to
17
Cu(OAc)
2
(1.0
2
3
equiv.)
1
1
2
8
9
0
Cu(OAc)
2
(1.0
2
3
H
2
O
120
120
120
[
12e]
equiv.)
promote the formation of 3d.
increased to 79% by the addition of silver salts (entries 2-3).
When Cu(OAc) was used, the yield was further improved to
2% (entry 4). Encouraged by these results, some other copper
Indeed, the yield of 3d was
Cu(OAc)
2
(1.0
2
3
Toluene
DMSO
equiv.)
2
Cu(OAc)
(1.0
2
2
3
8
equiv.)
.
salts such as CuCl
tested (entries 5-8), but Cu(OAc)
Subsequently, we examined the effect of base (entries 9-13),
CO was found to be the most suitable base (91%; entry 13).
2
, CuO, CuBr
2
and CuSO
4
5H
2
O were also
21
Cu(OAc)
2
(1.0
2
3
Dioxane 120
equiv.)
2
provided the best yield.
2
2
2
3
Cu(OAc)
2
(0.8
2
3
DMF
DMF
DMF
120
120
120
equiv.)
K
2
3
Cu(OAc)
2
(1.2
2
3
Control experiments indicated that base was essential for the
reaction, the product could be obtained with only 22% yield in
the absence of base (entry 14). As for the solvents and the
reaction temperature examination, it turned out that DMF
combined with 120°C afforded the best results (entries 15-21).
Finally, both the amount of copper catalyst and base were tested
equiv.)
24
Cu(OAc) (1.0
2
2
3
equiv.)
equiv.)
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), solvent (2 mL), stirred for 6
hours. Isolated yield.
b
(
entries 22-24). Hence, the optimized reaction conditions were
established as following, 4-chloro-2-iodoaniline (1) (0.5 mmol)
and sodium dimethyldithiocarbamate (2) (1.0 mmol), Cu(OAc)
0.5 mmol) and K CO (1.0 mmol) in DMF (2 mmol) at 120°C for
hours (entry 13).
With the optimized reaction conditions in hand, the scope and
functional group compatibility of the substrates were investigated.
Firstly, the reactions of sodium dimethyldithiocarbamate with
various substituted 2-iodoanilines were examined (Table 2). As
expected, the functional group tolerance on 2-iodoanilines was
remarkable. The reaction showed almost no obvious preference
toward either electron-withdrawing or electron-donating effects
of the substituents of 2-iodoanilines. Halide groups, such as F,
2
(
6
2
3
a
Table 1. Optimization of the reaction conditions.
Cl, Br and CF
3
yielded the desired products in 86-93% yields (3b,
3c, 3d, 3e, 3f), and other electron-withdrawing groups such as
2
NO and CN also showed excellent results (3g, 3h). As for 2-
Entry
Additive
Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
T
°C)
Yield
(%)
b
(
iodoanilines bearing 2, 4-dichloro groups, the yield of
corresponding product 3i decreased obviously to 66%. Diverse
electron-donating substituents also showed excellent results.
The m-methyl, p-methyl and p-methoxy furnished smoothly the
desired products 3j (94%), 3k (95%) and 3l (94%), respectively.
Unfortunately, heterocycle substrate did not provide the desired
product.
Encouraged by the above results, we further investigated the
scope and the generality of the method by varying various 2-
iodoanilines and sodium diethyldithiocarbamate trihydrate. The
results are summarized in Table 3. Note that all the substituted
1
2
3
4
5
6
7
8
9
CuI (0.1 equiv.)
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
CO
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
CO (2.0
equiv.)
3
(2.0
120
120
120
120
120
120
120
120
120
120
120
120
120
52
72
79
82
77
60
80
78
85
78
80
26
91
CuI(0.1 equiv.),
AgOTf (1.0 equiv.)
CuI(0.1 equiv.),
2
3
2
3
AgNO
Cu(OAc)
equiv.)
(1.0 equiv.)
3
(1.0 equiv.)
2
(1.0
2
3
CuCl
2
2
3
CuO (1.0 equiv.)
2
3
2
-iodoanilines bearing both electron-donating groups (m-Me, p-
Me and p-MeO) and electron-withdrawing groups (m-Cl, p-Cl, p-
Br, p-F, p-NO and p-CN) were able to couple with sodium
CuBr
2
(1.0 equiv.)
2
3
.
CuSO
4
5H
2
O (1.0
2
3
2
equiv.)
diethyldithiocarbamate trihydrate in good to excellent yields.
Notably, when the para-position of the phenyl ring was occupied
with a fluoro group, the reaction yield was achieved to 97% (3n).
Cu(OAc)
2
(1.0
CH
3
ONa (2.0
equiv.)
CO (2.0
2 3
equiv.)
1
1
1
1
0
1
2
3
Cu(OAc)
2
(1.0
Na
equiv.)
equiv.)
t
Table 2. One-pot cascade reactions of substituted 2-iodoanilines with sodium
Cu(OAc)
2
(1.0
KO Bu (2.0
a
dimethyldithiocarbamate.
equiv.)
equiv.)
Cu(OAc)
2
(1.0
Et
equiv.)
CO (2.0
3
N (2.0
equiv.)
Cu(OAc)
2
(1.0
K
2
3
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European Journal of Organic Chemistry
10.1002/ejoc.201801122
FULL PAPER
On the basis of the results obtained above and the studies
[
12e]
[14]
[15]
reported by Ma,
Zhang,
and Bao,
we proposed the
tentative mechanism for the formation of 2-aminobenzothiazoles
shown in Scheme 5. Initially, an Ullmann type C(aryl)-S bond
formation between 2-iodoaniline 1 with dithiocarbamate 2 is
[
12e, 15]
proceeded to give intermediate 3.
The amine group in 3
could in turn attack the C-S double bond to give cyclization
products 4, which then underwent intramolecular cyclization to
yield the desired 2-N-substituted benzothiazoles 5.
a
2
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cu(OAc) (1.0 equiv.),
2 3
K CO (2.0 equiv.), DMF (2.0 mL), 120 °C , Isolated yield based on 1.
Table 3. One-pot cascade reactions of substituted 2-iodoanilines with sodium
a
diethyldithiocarbamate trihydrate.
Scheme 5. The possible reaction mechanism.
Conclusions
In summary, we have developed a facile and efficient method
for the synthesis of 2-aminobenzothiazoles promoted by
copper(II). By using this simple “one-pot” operation manner, the
desired 2-aminobenzothiazoles were obtained smoothly starting
from 2-iodoanilines and sodium dithiocarbamates. The method
features ligand-free, mild reaction conditions, easily available
starting materials and good yields, illustrating its practical
synthetic value in some potentially biologically active
compounds. Further details and the development of related
applications for this protocol are under research in our laboratory.
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cu(OAc)
2
(1.0 equiv.),
K
2
CO (2.0 equiv.), DMF (2.0 mL), 120°C , Isolated yield based on 1.
3
Experimental Section
To explore the reaction mechanism in details, several control
experiments were performed and the results are shown in
Scheme 4. When 2-iodoaniline was treated with sodium
dimethyldithiocarbamate under the standard reaction conditions,
phenyl dimethyldithiocarbamate was isolated in 87% yield
General remarks: All starting materials were purchased from
commercial suppliers and used without further purification unless
otherwise stated. Yields refer to isolated compounds estimated to be
1

95% pure as determined by H NMR and capillary GC analysis. NMR
(
Scheme 4, eq 1), whereas only slightly aryl thiourea was
spectra were recorded on a Bruker AM400 NMR instrument in CDCl
3
obtained in the same reaction conditions when we treated
aniline with sodium dimethyldithiocarbamate (Scheme 4, eq 2).
This suggests that 2-iodobenzene is a much more efficient
coupling partner with sodium dimethyldithiocarbamate than
aniline.
using TMS as an internal standard. Chemical shifts are given in ppm and
coupling constants (J) are given in Hz. All melting points were
determined on a RY-1G melting point instrument without correction.
High-resolution mass spectra (HRMS) were recorded on a Finnigan MAT
9
5Q or Finnigan 90 mass instrument (ESI). TLC was performed using
aluminum plates coated with SiO (Merck 60, F-254) and visualized with
UV light at 254 nm. Column chromatography was performed on silica gel
200-300 mesh) with PE-EtOAc as eluent.
2
(
Typical procedure for the preparation of 2-aminobenzothiazoles
TP): 4-Chloro-2-iodoaniline (1, 0.5 mmol), sodium
dimethyldithiocarbamate (2, 1.0 mmol), Cu(OAc) (0.5 mmol) and K CO
(
Scheme 4. Control experiments by using 2-iodobenzene and aniline as
2
2
3
starting materials under standard reaction conditions.
(1.0 mmol) were added in a dried sealed tube equipped with a septum
and magnetic stirring bar, DMF (2.0 mL) was then added. The mixture
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European Journal of Organic Chemistry
10.1002/ejoc.201801122
FULL PAPER
o
[16]
was stirred at 120 C and checked by TLC until the starting material was
N,N-dimethyl-6-nitrobenzo[d]thiazol-2-amine (3g) : According to TP,
finished (about 6 h). The reaction was quenched with sat. NH
3.0 mL) and then extracted with ethyl acetate. The crude solution was
dried over anhydrous Na SO and evaporated under vacuum. The
4
Cl solution
the residue was purified by flash chromatography on silica gel (petroleum
(
ether/ethyl acetate = 7:1) to give the target compound 3g as a yellow
1
2
4
solid (103mg, 92%). M.p: 209-211°C; H NMR (400 MHz, CDCl
3
, TMS): δ
residue was purified by flash column chromatography to afford the
desired product 3d.
(ppm) 8.39 (s, 1H), 8.10 (d, 1H, J = 4.0 Hz), 7.41 (d, 1H, J = 4.0 Hz), 3.19
13
(s, 6H). C NMR (100 MHz, CDCl
30.2, 121.6, 116.8, 116.3, 39.5. HRMS (ESI) m/z [M+H] Calcd for
C H N O S (224.0488), found: 224.0480.
3
, TMS): δ (ppm) 171.1, 157.4, 140.4,
+
1
[
13e]
N,N-Dimethylbenzo[d]thiazol-2-amine (3a) : According to TP, the
9
10
3
2
residue was purified by flash chromatography on silica gel (petroleum
[
13e]
ether/ethyl acetate = 7:1) to give the target compound 3a as a brown
2-(Dimethylamino)benzo[d]thiazole-6-carbonitrile (3h) : According
to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 7:1) to give the target compound 3h as a
1
solid (74mg, 83%). M.p: 84-86°C; H NMR (400 MHz, CDCl
3
, TMS): δ
(
8
1
ppm) 7.47 (d, 2H, J = 8.0 Hz), 7.17 (t, 1H, J = 8.0 Hz), 6.39 (t, 1H, J =
13
1
.0 Hz), 3.04(s, 6H). C NMR (100 MHz, CDCl
52.4, 130.3, 125.3, 120.3, 120.0, 118.0, 39.5. HRMS (ESI) m/z [M+H]
S (179.0638), found: 179.0634.
3
, TMS): δ (ppm) 168.1,
pale-brown solid (84mg, 83%). M.p: 161-163°C; H NMR (400 MHz,
+
13
CDCl
(100 MHz, CDCl
18.8, 117.8, 102.2, 39.4. HRMS (ESI) m/z [M+H] Calcd for C10
(204.0590), found: 204.0597.
3
, TMS): δ (ppm) 7.75 (s, 1H), 7.44 (s, 2H), 3.16 (s, 6H). C NMR
Calcd for C
H N
9 11 2
3
, TMS): δ (ppm) 170.0, 155.6, 130.7, 129.1, 123.8,
+
1
10 3
H N S
[
13n]
6
-Fluoro-N,N-dimethylbenzo[d]thiazol-2-amine (3b) : According to
TP, the residue was purified by flash chromatography on silica gel
petroleum ether/ethyl acetate = 7:1) to give the target compound 3b as a
(
4,6-dichloro-N,N-dimethylbenzo[d]thiazol-2-amine (3i): According to
TP, the residue was purified by flash chromatography on silica gel
1
white solid (91mg, 93%). M.p: 118-120°C; H NMR (400 MHz, CDCl
3
,
TMS): δ (ppm) 7.35 (q, 1H), 7.16 (d, 1H, J = 8.0 Hz), 6.89 (t, 1H, J = 8.0
(petroleum ether/ethyl acetate = 7:1) to give the target compound 3i as a
13
1
Hz), 2.99 (s, 6H). C NMR (100 MHz, CDCl
3
, TMS): δ (ppm) 167.4,
57.1(d, 1C, J = 238.0 Hz), 148.4, 130.6 (d, 1C, J = 11.0 Hz), 118.1(d,
C, J = 8.0 Hz), 112.5(d, 1C, J = 24.0 Hz), 106.4(d, 1C, J = 27.0 Hz),
white solid (81mg, 66%). M.p: 118-120°C; H NMR (400 MHz, CDCl
3
,
13
1
1
3
1
TMS): δ (ppm) 7.35 (s, 1H), 7.22 (d, 1H, J = 4.0 Hz), 3.13 (s, 6H).
C
NMR (100 MHz, CDCl , TMS): δ (ppm) 168.7, 149.0, 132.9, 126.2, 125.5,
3
+
+
9 2
9.3. HRMS (ESI) m/z [M+H] Calcd for C H10FN S (197.0543), found:
9 9 2 2
123.2, 118.8, 40.1. HRMS (ESI) m/z [M+H] Calcd for C H Cl N S
97.0549.
(246.9858), found: 246.9854.
[
13e]
[13e]
5
-Chloro-N,N-dimethylbenzo[d]thiazol-2-amine (3c) : According to
N,N,5-trimethylbenzo[d]thiazol-2-amine (3j) : According to TP, the
TP, the residue was purified by flash chromatography on silica gel
petroleum ether/ethyl acetate = 7:1) to give the target compound 3c as a
residue was purified by flash chromatography on silica gel (petroleum
(
ether/ethyl acetate = 7:1) to give the target compound 3j as a pale-white
1
1
pale-white solid (91mg, 86%). M.p: 107-109°C; H NMR (400 MHz,
CDCl , TMS): δ (ppm) 7.46 (s, 1H), 7.39 (d, 1H, J = 4.0 Hz), 6.94 (d, 1H,
J = 4.0 Hz), 3.12 (s, 6H). C NMR (100 MHz, CDCl
ppm)168.8, 153.2, 130.8, 128.3, 120.2, 120.0, 117.7, 39.2. HRMS (ESI)
solid (90mg, 94%). M.p: 117-118°C; H NMR (400 MHz, CDCl
3
, TMS): δ
3
(ppm) 7.35 (t, 2H, J = 8.0 Hz), 6.79 (d, 1H, J = 4.0 Hz), 3.07 (s, 6H), 2.31
13
13
3
, TMS): δ
(s, 3H). C NMR (100 MHz, CDCl
126.9, 121.2, 119.2, 118.3, 39.2, 20.6. HRMS (ESI) m/z [M+H] Calcd for
10 13 2
C H N S (193.0794), found: 193.0798.
3
, TMS): δ (ppm) 168.1, 152.5, 134.9,
+
(
+
m/z [M+H] Calcd for C
9 2
H10ClN S (213.0248), found: 213.0241.
[
13e]
[13e]
6
-Chloro-N,N-dimethylbenzo[d]thiazol-2-amine (3d) : According to
TP, the residue was purified by flash chromatography on silica gel
petroleum ether/ethyl acetate = 7:1) to give the target compound 3d as a
N,N,6-Trimethyl-2-benzothiazolamine (3k) : According to TP, the
residue was purified by flash chromatography on silica gel (petroleum
(
ether/ethyl acetate = 7:1) to give the target compound 3k as a pale-
1
1
pale-white solid (96mg, 91%). M.p: 100-102°C; H NMR (400 MHz,
CDCl , TMS): δ (ppm) 7.45 (s, 1H), 7.38 (d, 1H, J = 4.0 Hz), 7.15 (d, 1H,
J = 4.0 Hz), 3.10 (s, 6H). C NMR (100 MHz, CDCl
67.8, 150.7, 131.2, 125.4, 125.0, 119.3, 118.3, 39.2. HRMS (ESI) m/z
brown solid (91mg, 95%). M.p: 83-85°C; H NMR (400 MHz, CDCl
3
,
3
TMS): δ (ppm) 7.37 (d, 1H, J = 4.0 Hz), 7.28 (s, 1H), 6.99 (d, 1H, J = 4.0
Hz), 3.06 (s, 6H), 2.28 (s, 3H). C NMR (100 MHz, CDCl
(ppm) 167.3, 149.9, 130.1, 129.6, 126.1, 119.7, 117.4, 39.2, 20.2. HRMS
13
13
3
, TMS): δ (ppm)
3
, TMS): δ
1
+
+
[M+H] Calcd for C
9
H10ClN
2
S (213.0248), found: 213.0243.
(ESI) m/z [M+H] Calcd for C10
H N
13 2
S (193.0794), found: 193.0790.
[
13e]
[17]
6
-Bromo-N,N-dimethylbenzo[d]thiazol-2-amine (3e) : According to
TP, the residue was purified by flash chromatography on silica gel
petroleum ether/ethyl acetate = 7:1) to give the target compound 3e as a
6-methoxy-N,N-dimethylbenzo[d]thiazol-2-amine (3l) : According to
TP, the residue was purified by flash chromatography on silica gel
(
(petroleum ether/ethyl acetate = 7:1) to give the target compound 3l as a
light-yellow solid (98mg, 94%). M.p: 91-93°C; H NMR (400 MHz, CDCl
TMS): δ (ppm) 7.38 (d, 1H, J = 4.0 Hz), 7.04 (d, 1H, J = 1.0 Hz), 6.80 (m,
1H), 3.71, (s, 3H), 3.05 (s, 6H). C NMR (100 MHz, CDCl
1
1
pale-brown solid (113mg, 88%). M.p: 106-108°C; H NMR (400 MHz,
, TMS): δ (ppm) 7.61 (s, 1H), 7.32 (m, 2H), 3.12 (s, 6H). C NMR
100 MHz, CDCl , TMS): δ (ppm) 168.4, 151.5, 132.2, 128.7, 122.6,
3
,
13
CDCl
(
1
3
13
3
3
, TMS): δ
+
9 2
19.4, 112.7, 39.8. HRMS (ESI) m/z [M+H] Calcd for C H10BrN S
(ppm) 166.5, 153.7, 146.3, 130.9, 118.1, 112.5, 104.3, 54.9, 39.2. HRMS
+
(256.9743), found: 256.9749.
(ESI) m/z [M+H] Calcd for C10
H N
13 2
OS (209.0743), found: 209.0749.
[
16]
[13e]
6-Trifluoromethyl -N,N-dimethylbenzo[d]thiazol-2-amine
(3f)
:
N,N-Diethyl-2-benzothiazolamine (3m)
: According to TP, the
According to TP, the residue was purified by flash chromatography on
residue was purified by flash chromatography on silica gel (petroleum
silica gel (petroleum ether/ethyl acetate = 7:1) to give the target
ether/ethyl acetate = 7:1) to give the target compound 3m as a colorless
1
1
compound 3f as a light-yellow solid (108mg, 88%). M.p: 112-114°C;
NMR (400 MHz, CDCl
H
oil (97mg, 94%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 7.47 (s, 2H),
13
3
, TMS): δ (ppm) 7.76 (s, 1H), 7.47 (m, 2H), 3.13 (s,
H). C NMR (100 MHz, CDCl , TMS): δ (ppm) 169.3, 154.8, 130.2,
7.18 (s, 1H), 6.94 (s, 1H), 3.48 (d, 4H, J = 4.0 Hz), 1.19 (s, 6H). C NMR
(100 MHz, CDCl , TMS): δ (ppm) 166.7, 152.7, 130.0, 125.1, 120.0,
13
6
1
3
3
3
+
23.6(d, 1C, J = 270.0 Hz), 122.1(d, 1C, J = 3.0 Hz), 121.7(d, 1C, J =
15 2
119.9, 117.9, 44.7, 12.2. HRMS (ESI) m/z [M+H] Calcd for C11H N S
+
2.0 Hz)， 117.4，116.9(d, 1C, J = 4.0 Hz). HRMS (ESI) m/z [M+H]
(207.0951), found: 207.0957.
10 3 2
Calcd for C10H F N S (247.0512), found: 247.0517.
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European Journal of Organic Chemistry
10.1002/ejoc.201801122
FULL PAPER
N,N-diethyl-6-fluorobenzo[d]thiazol-2-amine (3n): According to TP,
the residue was purified by flash chromatography on silica gel (petroleum
146.6, 130.6, 117.9, 122.3, 104.3, 54.9, 44.3, 11.9. HRMS (ESI) m/z
+
17 2
[M+H] Calcd for C12H N S (221.1107), found: 221.1100.
ether/ethyl acetate = 7:1) to give the target compound 3n as a yellow oil
1
(
7
109mg, 97%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 7.34 (m, 1H),
[13e]
N,N-diethyl-6-methylbenzo[d]thiazol-2-amine (3u) : According to TP,
.18 (t, 1H, J = 4.0 Hz), 6.89 (m, 1H), 3.44 (d, 4H, J = 4.0 Hz), 1.17 (t, 6H,
the residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 7:1) to give the target compound 3u as a colorless
, TMS): δ (ppm) 7.40 (t, 2H,
J = 12.0 Hz), 6.84 (d, 1H, J = 4.0 Hz), 3.54 (m, 4H), 2.38 (s, 3H), 1.26 (t,
13
J = 8.0 Hz). C NMR (100 MHz, CDCl
C, J = 237.0 Hz), 148.8, 130.3 (d, 1C, J = 10.0 Hz), 117.8(d, 1C, J = 9.0
Hz), 112.3 (d, 1C, J = 23.0 Hz), 106.3 (d, 1C, J = 27.0 Hz), 44.4, 11.9.
3
, TMS): δ (ppm) 165.9, 156.8 (d,
1
1
oil (100mg, 91%). H NMR (400 MHz, CDCl
3
+
13
2
HRMS (ESI) m/z [M+H] Calcd for C11H14FN S (225.0856), found:
6
H, J = 4.0 Hz). C NMR (100 MHz, CDCl
3
, TMS): δ (ppm) 165.8, 149.9,
2
25.0855.
1
29.5, 129.4, 126.0, 119.7, 117.1, 44.4, 20.2, 11.9. HRMS (ESI) m/z
+
17 2
[M+H] Calcd for C12H N S (221.1107), found: 221.1103.
[
13e]
5-chloro-N,N-diethylbenzo[d]thiazol-2-amine (3o) : According to TP,
the residue was purified by flash chromatography on silica gel (petroleum
N,N-diethyl-6-methoxybenzo[d]thiazol-2-amine (3v): According to TP,
ether/ethyl acetate = 7:1) to give the target compound 3o as a light-
the residue was purified by flash chromatography on silica gel (petroleum
1
yellow solid (114mg, 95%). M.p: 104-105°C; H NMR (400 MHz, CDCl
3
,
ether/ethyl acetate = 7:1) to give the target compound 3v as a yellow oil
1
TMS): δ (ppm) 8.18 (s, 1H), 7.21 (t, 2H, J = 8.0 Hz), 6.99 (d, 1H, J = 4.0
(
100mg, 85%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 7.35 (t, 1H, J =
13
Hz), 3.71 (d, 4H, J = 4.0 Hz), 1.27 (t, 6H, J = 8.0 Hz). C NMR (100 MHz,
CDCl , TMS): δ (ppm) 178.1, 136.5, 131.8, 128.7, 125.5, 124.7, 124.0,
4.8, 11.7. HRMS (ESI) m/z [M+H] Calcd for C11
found: 241.0554.
4
1
1
.0 Hz), 7.04 (d, 1H, J = 1.2 Hz), 6.79 (m, 1H), 3.72 (s, 3H), 3.45 (m, 4H),
13
3
.18 (t, 6H, J = 8.0 Hz). C NMR (100 MHz, CDCl
3
, TMS): δ (ppm) 165.9,
+
4
2
H14ClN S (241.0561),
54.5, 147.5, 131.5, 118.8, 113.2, 105.3, 55.9, 45.2, 12.9. HRMS (ESI)
+
17 2
m/z [M+H] Calcd for C12H N OS (237.1056), found: 237.1051.
[
13e]
6
-chloro-N,N-diethylbenzo[d]thiazol-2-amine (3p) : According to TP,
the residue was purified by flash chromatography on silica gel (petroleum
Acknowledgements
ether/ethyl acetate = 7:1) to give the target compound 3p as a yellow oil
1
(
114mg, 95%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 7.44 (s, 1H),
7
6
1
.34 (d, 1H, J = 4.0 Hz), 7.13 (d, 1H, J = 4.0 Hz), 3.47 (m, 4H), 1.19 (t,
We thank the foundation support from National Natural Science
Foundation of China (21302150), foundation of Chen-Guang
program from Hubei Association for Science and Technology,
foundation of Chutian distinguished fellow from Hubei Provincial
Department of Education, foundation of High-end Talent
Cultivation Program from Wuhan Institute of Technology. Z.-B. D.
acknowledges the Humboldt Foundation and China Scholarship
Council for a fellowship. H. Z. thanks the Support of Graduate
Innovative Fund of Wuhan Institute of Technology.
13
H, J = 8.0 Hz). C NMR (100 MHz, CDCl
30.9, 125.4, 124.8, 119.3, 118.2, 44.7, 12.0. HRMS (ESI) m/z [M+H]
S (241.0561), found: 241.0564.
3
, TMS): δ (ppm) 166.6, 151.0,
+
Calcd for C11H14ClN
2
[
13e]
6-bromo-N,N-diethylbenzo[d]thiazol-2-amine (3q) : According to TP,
the residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 7:1) to give the target compound 3q as a yellow oil
1
(122mg, 86%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 7.58 (s, 1H),
13
7.28 (m, 2H), 3.46 (m, 4H), 1.19 (t, 6H, J = 8.0 Hz). C NMR (100 MHz,
3
CDCl , TMS): δ (ppm) 166.4, 151.1, 131.2, 128.0, 122.0, 118.6, 111.9,
+
4
4.6, 11.9. HRMS (ESI) m/z [M+H] Calcd for C11
2
H14BrN S (285.0056),
Keywords: 2-aminobenzothiazole • copper • one-pot • 2-
iodoanilines • dithiocarbamate
found: 285.0057.
[
18]
N,N-diethyl-6-nitrobenzo[d]thiazol-2-amine (3r) : According to TP,
the residue was purified by flash chromatography on silica gel (petroleum
[
1]
a) M. S. Gomaa, J. L. Armstrong, B. Bobillon, G. J. Veal, A. Brancale, C.
P. Redfern, C. Simons, Bioorg. Med. Chem. 2008, 16, 8301–8313; b) S.
K. Sahoo, A. Banerjee, S. Chakraborty, B. K. Patel, ACS Catal. 2012, 2,
ether/ethyl acetate = 7:1) to give the target compound 3r as a pale-yellow
1
oil (109mg, 87%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 8.41 (d, 1H,
544-551; c) S. K. Sahoo, N. Khatun, A. Gogoi, A. Deb, B. K. Patel, RSC
J = 1.0 Hz), 8.11 (m, 1H), 7.41 (d, 1H, J = 4.0 Hz), 3.55 (d, 4H, J = 4.0
13
Adv. 2013, 3, 438-446.
Hz), 1.25 (t, 6H, J = 8.0 Hz). C NMR (100 MHz, CDCl
3
, TMS): δ (ppm)
[
2]
a) R. A. Glennon, J. J. Gaines, M. E. Rogers, J. Med. Chem. 1981, 24,
766-769; b) A. D. Jordan, C. Luo, A. B. Reitz, J. Org. Chem. 2003, 68,
1
70.7, 158.6, 141.2, 130.9, 122.4, 117.6, 117.0, 46.0, 12.7. HRMS (ESI)
+
m/z [M+H] Calcd for C11
14 3 2
H N O S (252.0801), found: 252.0804.
8
693-8696; c) A. R. Katritzky, D. O. Tymoshenko, D. Monteux, V.
Vvedensky, G. Nikonov, C. B. Cooper, M. Deshpande, J. Org. Chem.
000, 65, 8059-8062.
2-(diethylamino)benzo[d]thiazole-6-carbonitrile (3s): According to TP,
2
the residue was purified by flash chromatography on silica gel (petroleum
[
[
3]
4]
B. Gurupadyya, M. Gopal, B. Padmashali, Y. Manohara, Indian J.
Pharm. Sci. 2008, 70, 572–577.
ether/ethyl acetate = 7:1) to give the target compound 3s as a yellow oil
1
(
7
97mg, 84%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 7.74 (s, 1H),
T. Soneda, H. Takeshita, Y. Kagoshima, Y. Yamamoto, T. Hosokawa, T.
Konosu, N. Masuda, T. Uchida, I. Achiwa, J. Kuroyanagi, T. Fujisawa, A.
Yokomizo, T. Noguchi, WO 2009084614, 2009.
13
.42 (s, 2H), 3.51 (d, 4H, J = 4.0 Hz), 1.22 (t, 6H, J = 8.0 Hz). C NMR
(
1
100 MHz, CDCl , TMS): δ (ppm) 168.7, 155.8, 130.3, 128.9, 123.6,
18.8, 117.6, 101.9, 44.9, 11.8. HRMS (ESI) m/z [M+H] Calcd for
3
+
[
[
5]
6]
S. Massari, D. Daelemans, M. L. Barreca, A. Knezevich, S. Sabatini, V.
Cecchetti, A. Marcello, C. Pannecouque, O. Tabarrini, J. Med. Chem.
12 14 3
C H N S (232.0903), found: 232.0897.
2010, 53, 641-648.
[
13e]
N,N-diethyl-5-methylbenzo[d]thiazol-2-amine (3t) : According to TP,
a) M. E. McDonnell, M. D. Vera, B. E. Blass, J. C. Pelletier, R. C. King,
C. F. Metzler, G. R. Smith, J. Wrobel, S. Chen, B. A. Wall, A. B. Reitz,
Bioorg. Med. Chem. 2012, 20, 5642-5648; b) B. C. Cheah, S. Vucic, A.
V. Krishnan, M. C. Kiernan, Curr. Med. Chem. 2010, 17, 1942-1959.
a) D. S. Bose, M. Idrees, Tetrahedron Lett. 2007, 48, 669-672; b) D. S.
Bose, M. Idrees, J. Org. Chem. 2006, 71, 8261-8263; c) N. K. D. Riley,
the residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 7:1) to give the target compound 3t as a colorless
1
oil (101mg, 92%). H NMR (400 MHz, CDCl
3
, TMS): δ (ppm) 7.36 (t, 2H,
J = 8.0 Hz), 6.79 (d, 1H, J = 4.0 Hz), 3.49 (m, 4H), 2.33 (s, 3H), 1.20 (t,
[
7]
13
6
3
H, J = 8.0 Hz). C NMR (100 MHz, CDCl , TMS): δ (ppm) 165.0, 153.6,
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European Journal of Organic Chemistry
10.1002/ejoc.201801122
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European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Text for Table of Contents
Key Topic*
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
NOTE: the final letter height should
not be less than 2 mm.))
*one or two words that highlight the emphasis of the paper or the field of the study
Layout 2:
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Cyclization:
synthesis
of
2-
aminobenzothiazoles*
H. Zhu, S.-B. Zhang, X. Liu, Y. Cheng,
H.-Y. Peng, Z.-B. Dong*
Page No. – Page No.
Text for Table of Contents
Copper(II)-Promoted
Cascade
Synthesis of 2-Aminobenzothiazoles
Starting from 2-Iodoanilines and
Sodium Dithiocarbamates
*one or two words that highlight the emphasis of the paper or the field of the study
A facile and efficient formation of 2-aminobenzothiazoles by a copper(II)-promoted one-pot cascade process was developed.
The desired 2-aminobenzothiazoles were synthesized in good to excellent yields (up to 97%) in the presence of Cu(OAc) and
CO , a variety of functional groups on 2-iodoanilines could be tolerated. The method features ligand-free, mild reaction
2
K
2
3
conditions and good yields, illustrating its practical synthetic value in some potentially biologically active compounds.
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