Palladium-Catalyzed Synthesis of 2-Aminobenzothiazoles through Tandem Reaction

Article abstract of DOI:10.1055/s-0036-1588835

A variety of 2-aminobenzothiazoles were synthesized by using 2-chloroanilines and dithiocarbamates through a tandem approach in the presence of Pd(PPh ₃) ₄ and t -BuOK. The facile and efficient protocol enabled the reaction to proceed at a good rate with excellent yields.

Full text of DOI:10.1055/s-0036-1588835

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
feature
A
en
W. Xu et al.
Feature
Synthesis
Palladium-Catalyzed Synthesis of 2-Aminobenzothiazoles
through Tandem Reaction
Wan Xua
Meng-Tian Zenga
by tandem cyclization
R2
Min Liua
Sha-Sha Liua
Yue-Sheng Lib
Zhi-Bing Dong*a
R2
N
NH2
Cl
S
N
Pd(PPh3)4, t-BuOK
R2
R1
N
R1
+
S
S
DMSO, 100 °C
3.5–4.5 h
R2
73–91% yield, 15 examples
R1 = Br, Cl, Me, MeO, CN,...
a School of Chemistry and Environment Engineering, Wuhan
Institute of Technology, 430074, P. R. of China
dzb04982@wit.edu.cn
b Nonpower Nuclear Technology Collaborative Innovation
Center, Hubei University of Science & Technology, Xianning
437100, P. R. of China
R
2 = Me, Et
Received: 18.03.2017
Accepted after revision: 24.04.2017
Published online: 24.05.2017
examined (Table 1, entries 1–8). We are pleased to find that
2-(dimethylamino)benzothiazole could be afforded in 82%
yield in the presence of Pd(PPh3)4 and t-BuOK (entry 4)
when the reaction was performed in dimethyl sulfoxide
(DMSO). Copper catalysts did not catalyze this reaction and
some other palladium catalysts displayed less activity in
the transformation, providing the 2-aminobenzothiazole in
poor to moderate yields (entries 5–7). Organic and inorgan-
ic bases were screened for the model reaction. For example,
triethylamine (NEt3), NaH, CH3ONa, Cs2CO3, NaOH, and
K2CO3 (entries 9–14) were tested and t-BuOK was found to
be the most suitable base to promote the reaction. Several
other solvents were also tested in this reaction, and all
proved less efficient (entries 15–19). Among the solvents
and reaction temperatures examined (entries 20–23),
DMSO proved to be the most suitable solvent and the reac-
tion was optimal at 100 °C. The use of 3 equiv of t-BuOK
was crucial to achieve complete conversion. When 2 equiv
was used, the product yield was much lower (25%) (entry
24) and we could not detect the target product when the
base loading was decreased to 1 equiv (entry 25).
With the optimal reaction conditions in hand, we began
to establish the scope of the reaction with respect to the
substrate 2-chloroanilines and dithiocarbamates. A number
of 2-chloroaniline derivatives (Table 2, 1a–h) were investi-
gated in the reaction with dithiocarbamates (Table 2, 2a–b).
The results revealed that the optimal conditions had broad
substrate compatibility. Substrates 1c, 1b and 1d, having ei-
ther an electron-donating group or an electron-poor group
para to the chloro group, reacted with dithiocarbamate (2a)
smoothly to furnish the desired products in 82, 73, and 79%
yield, respectively (entries 3, 2, and 4).
DOI: 10.1055/s-0036-1588835; Art ID: ss-2017-z0171-fa
Abstract A variety of 2-aminobenzothiazoles were synthesized by us-
ing 2-chloroanilines and dithiocarbamates through a tandem approach
in the presence of Pd(PPh3)4 and t-BuOK. The facile and efficient proto-
col enabled the reaction to proceed at a good rate with excellent yields.
Key words potassium tert-butoxide, palladium, chloroloaniline, ami-
nobenzothiazole, tandem
Benzothiazoles are an important class of heterocyclic
compound that have a wide range of applications as key
building blocks in many trade drugs. They can exhibit a
wide range of biological activities such as antitumor,1 anti-
microbial,2 antibubercular,3 antimalarial,4 anti-inflammato-
ry,5 analgesic,6 and antibacterial7 action. There are mainly
two traditional approaches to prepare the 2-substituted
benzothiazole ring system. One of which is a condensation
reaction of 2-aminothiophenols with aldehydes or carbox-
ylic acid derivatives under strongly acidic conditions,8–19
and the second approach is through cyclization of thio-
benzanilides.20–27 Other procedures such as cyclization of
N-(2-halo)arylthioureas (halogen=Br, I) or direct intramo-
lecular C–S bond formation through C–H functionalization
of N-arylthioureas catalyzed by transition metals, have en-
riched the scope of available preparation methods.28,29
However, few examples have been reported for the synthe-
sis of 2-aminobenzothiazoles that use 2-chloroloanilines as
starting materials.30 Herein, we present a facile and effi-
cient protocol for the synthesis of 2-aminobenzothiazoles
by palladium-catalyzed tandem reaction.
Initially, we used 2-chloroaniline (1a) and dithiocarba-
mate (2a) as starting materials to optimize the reaction
conditions. Various copper and palladium catalysts were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
W. Xu et al.
Feature
Synthesis
Table 1 Screening Reaction Conditions with 2-Chloroaniline (1a) and
Dithiocarbamate (2a)a
Entry Catalyst
Base (equiv)
Solvent
Temp. (°C) Yield (%)b
20
21
22
23
24
25
Pd(PPh3)4
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (2.0)
t-BuOK (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
60
80
24
39
68
81
25
–
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
NH2
S
N
conditions
N
S
+
N
90
S
Cl
110
100
100
1a
2a
Entry Catalyst
Base (equiv)
Solvent
Temp. (°C) Yield (%)b
a Reaction conditions: 1a (1.0 mmol), 1b (1.5 mmol), [Cat.] (5 mmol%), sol-
1
2
CuBr
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
NEt3 (3.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMAC
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
–
vent (3.0 mL), 4.5 h.
CuO
–
b Isolated yield.
3
Cu(OTf)2
–
4
Pd(PPh3)4
PdCl2
82
19
24
61
–
However, substrate 1h, having an electron-withdrawing
group meta to the chloro afforded the corresponding prod-
uct in 76% yield (Table 2, entry 8). Substrates 1e and 1g,
having an electron-donating (methyl or methoxy group)
group meta to the chloro furnished the corresponding prod-
uct in 84% and 91% yield, respectively (entry 5 and 7). Com-
pared with 1d, substrate 1f, having a moderate electron-
withdrawing group meta to the chloro, afforded the desired
product in 88% yield (entry 6). Subsequently, the reaction of
dithiocarbamate 2b was examined under the optimal con-
ditions (entries 9–15). We were pleased to find that diethyl
dithiocarmamate (2b) was a good coupling partner to react
with 2-chloroanilines, affording the corresponding prod-
ucts with good to excellent yields. Notably, 1g reacted well
to provide methoxy-substituted benzothiazole 3o in a re-
markable 91% yield (entry 15). The protocol could also be
applied to the unreactive 3-amino-2-chloropyridine. Under
5
6
PdBr2
7
Pd(dba)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
8
9
32
44
16
45
39
34
12
8
10
11
12
13
14
15
16
17
18
19
NaH (3.0)
CH3ONa (3.0)
Cs2CO3 (3.0)
NaOH (3.0)
K2CO3 (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
CH3CN
CH2Cl2
PhCH3
11
–
62
Biographical Sketch
Wan Xu was born in 1990 in
Hubei, China. He received his
Bachelor’s degree from Wuhan
Institute of Bioengineering in
2013. He is currently a second-
year graduate student with Prof.
Dong at Wuhan Institute of
Technology (WIT).
Zhi-Bing Dong is a Chutian
Distinguished Professor at Wu-
han Institute of Technology
(WIT). He spent one year as a
visiting PhD student (2007–
2008) with Prof. Paul Knochel at
Ludwig-Maximilians-University,
and then obtained his PhD in
2008. Later he joined Prof. Shu
Kobayashi’s group at the Uni-
versity of Tokyo (2010–2011),
and worked with Prof. Carsten
Bolm at RWTH as an Alexander
von Humboldt Postdoctoral Fel-
low (2011–2012). His research
interests deal mainly with the
transition metal catalyzed C–X
(X = S, O, N, C) bond-formation
reactions and organic reactions
in water.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
W. Xu et al.
Feature
Synthesis
NH2
N
S
H
N
S
N
add Pd(PPh3)4
t-BuOK, DMSO
N
N
+
S
100 °C, 4h
5 h
ref. 28b
Cl
S
Cl
74%
step 1: base-promoted
synthesis of 2-chloro-
arylthiourea
step 2: Pd-catalyzed
cyclization
Scheme 1 Proposed mechanism
H
the standard reaction conditions, 3-amino-2-chloropyri-
dine (1h) reacted with 2a to give the desired product 3p
with satisfactory yield (92%; entry 16).
NH2
Cl
N
N
S
N
t-BuOK, DMSO
+
S
100 °C, 4h
S
Cl
A plausible mechanism for the reaction is proposed
(Scheme 1). The first step is the formation of aryl thiourea
promoted by base, which is subsequently transformed to
aryl-isothiourea. The second step is the palladium-
catalyzed intramolecular cross-coupling reaction28b which
allows the aryl-isothiourea to afford 2-aminobenzothiazole
smoothly.
To verify the mechanism, we conducted a control exper-
iment (Scheme 2) with no addition of palladium catalyst. In
this case, N-(2-chloro)arylthiourea was obtained as the key
intermediate (isolated yield: 91%) and the by product (thio-
phenol) was detected in the aqueous phase by GC-MS.
The control experiment shown in Scheme 3 further il-
lustrates our proposal. Palladium catalyst was added when
the generation of (2-chloro)arylthiourea was finished
(checked by TLC), and the desired target molecule (2-
aminobenzothiazole) could be furnished by Pd-catalyzed
cyclization28b with 74% isolated yield.
Isolation yield: 91%
Scheme 2 A control experiment: isolation of the key intermediate
tional groups are tolerated, giving access to a wide range of
substituted 2-aminobenzothiazoles. The protocol has prac-
tical synthetic value for the preparation of biologically and
pharmaceutically active compounds. Further details and
the development of related applications for this protocol
are under research in our laboratory.
NH2
S
N
t-BuOK, DMSO
100 °C, 4h
crude intermediate
without isolation
+
S
Cl
full conversion
N
add Pd(PPh3)4
5 h
N
S
In summary, we have developed a new protocol for the
synthesis of 2-aminobenzothiazoles starting from substi-
tuted 2-chloroanilines and dithiocarbamates. Various func-
ref. 28b
Isolation yield: 74%
Scheme 3 A control experiment: subsequent Pd-catalyzed cyclization
Table 2 Pd(PPh3)4-Catalyzed Tandem Reactions of 2-Chloroanilines (1) with Dithiocarbamates (2)a
R2
R2
R2
NH2
Cl
S
N
N
S
Pd(PPh3)4, t-BuOK
DMSO, 100 °C
3.5–4.5 h
R2
R1
+
R1
N
S
2
1
Entry
1
2-Chloroaniline
Dithiocarbamate
Product
Yield (%)b
82
NH2
N
S
N
N
S
S
Cl
3a
1a
2a
2a
2a
NH2
N
S
N
N
2
3
73
82
S
Br
3b
S
S
Br
Cl
1b
NH2
Cl
N
S
S
N
N
3c
1c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
W. Xu et al.
Feature
Synthesis
Table 2 (continued)
Entry
2-Chloroaniline
Dithiocarbamate
Product
Yield (%)b
NH2
Cl
N
S
S
S
S
S
S
N
N
N
N
N
N
4
5
6
7
8
79
84
88
91
76
Cl
3d
Cl
1d
S
S
S
S
S
2a
2a
2a
2a
2a
NH2
N
S
N
Cl
3e
1e
Cl
NH2
Cl
N
S
N
Cl
3f
1f
H3CO
NH2
Cl
H3CO
N
N
S
3g
1g
NH2
N
N
S
NC
3h
NC
1h
Cl
NH2
Cl
N
S
S
N
N
9
10
11
12
13
14
86
83
89
84
82
87
S
3i
1a
2b
2b
2b
2b
2b
2b
NH2
Cl
N
S
S
S
N
N
N
N
S
Br
3j
Br
1b
S
S
S
NH2
N
S
N
Cl
3k
1c
NH2
Cl
N
S
N
Cl
3l
Cl
1d
NH2
Cl
N
S
S
S
N
N
N
S
S
3m
1e
Cl
NH2
Cl
N
S
N
Cl
3n
1f
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
W. Xu et al.
Feature
Synthesis
Table 2 (continued)
Entry
2-Chloroaniline
Dithiocarbamate
Product
Yield (%)b
H3CO
NH2
Cl
H3CO
N
S
S
N
N
15
91
92
S
3o
1g
2b
2a
NH2
Cl
N
S
S
N
16c
S
N
3p
N
1h
a Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), Pd(PPh3)4 (5 mol%), t-BuOK (3.0 mmol), DMSO (3 mL), 100 °C.
b Isolated yield.
c An example of the reaction with a heterocycle.
13C NMR (100 MHz, CDCl3): δ = 168.80, 151.81, 132.51, 129.22,
123.12, 119.80, 113.26, 40.33.
All reactions were carried out in dried glassware fitted with septum
caps. All starting materials were purchased from commercial suppli-
ers and used without further purification, unless otherwise stated.
DMSO was dried with molecular sieves. Yields refer to isolated com-
pounds estimated to be >95% pure as determined by 1H NMR and cap-
illary GC analysis.
HRMS (ESI): m/z calcd for C9H9BrN2S: 255.9670; found: 255.9682.
N,N-6-Trimethylbenzo[d]thiazol-2-amine (3c)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
Preparation of 2-Aminobenzothiazoles with Potassium tert-Bu-
toxide and Tetrakis(triphenylphosphine)palladium; Typical Pro-
cedure
Yield: 157 mg (82%); pale-brown solid; mp 82–84 °C.
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 4.0 Hz, 1 H), 7.28 (s, 1 H),
7.00 (d, J = 3.8 Hz, 1 H), 3.05 (s, 6 H), 2.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.11, 150.72, 131.06, 130.61,
127.11, 120.72, 118.34, 40.36, 20.86.
In a dried tube, equipped with a magnetic stirrer and a septum, 2-
chloroaniline (1.0 mmol) was dissolved in DMSO (3 mL), and t-BuOK
(3.0 mmol) was added. The mixture was stirred for 5 min, then dith-
iocarbamate (1.5 mmol) and tetrakis(triphenylphosphine) palladium
(5 mol %) were added. The reaction mixture was heated at 100 °C and
the progress of the reaction was checked by TLC until the starting ma-
terial was consumed. The mixture was cooled to r.t., and the reaction
was quenched with sat. NH4Cl solution (5 mL). The mixture was ex-
tracted with EtOAc, dried over anhydrous Na2SO4 and evaporated un-
der vacuum. The residue was purified by flash column chromatogra-
phy to afford the desired product.
HRMS (ESI): m/z calcd for C10H12N2S: 192.0721; found: 192.0713.
6-Chloro-N,N-dimethylbenzo[d]thiazol-2-amine (3d)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
Yield: 168 mg (79%); pale-white solid; mp 100–102 °C.
1H NMR (400 MHz, CDCl3): δ = 7.51 (s, 1 H), 7.43 (d, J = 4.4 Hz, 1 H),
7.20 (d, J = 4.4 Hz, 1 H), 3.15 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 168.57, 151.64, 132.14, 126.38,
N,N-Dimethylbenzo[d]thiazol-2-amine (3a)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
125.97, 120.29, 119.33, 40.36.
Yield: 146 mg (82%); brown solid; mp 83–85 °C.
HRMS (ESI): m/z calcd for C9H9ClN2S: 212.0175; found: 212.0166.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.6 Hz, 2 H), 7.28 (t, J =
8.0 Hz, 1 H), 7.09 (t, J = 6.8 Hz, 1 H), 3.21 (s, 6 H).
N,N-5-Trimethylbenzo[d]thiazol-2-amine (3e)
13C NMR (100 MHz, CDCl3): δ = 168.32, 152.68, 130.44, 125.72,
120.72, 120.40, 118.50, 39.77.
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
HRMS (ESI): m/z calcd for C9H10N2S: 178.0565; found: 178.0572.
Yield: 161 mg (84%); pale-white solid; mp 115–116 °C.
1H NMR (400 MHz, CDCl3): δ = 7.33 (t, J = 13.60 Hz, 2 H), 6.78 (d, J =
6-Bromo-N,N-dimethylbenzo[d]thiazol-2-amine (3b)
3.8 Hz, 1 H), 3.07 (s, 6 H), 2.30 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.06, 153.28, 135.88, 127.60,
122.17, 120.16, 119.27, 39.67, 21.56.
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
Yield: 187 mg (73%); pale-brown solid; mp 107.0–109 °C.
1H NMR (400 MHz, CDCl3): δ = 7.66 (s, 1 H), 7.42–7.34 (m, 2 H), 3.19
HRMS (ESI): m/z calcd for C10H12N2S: 192.0721; found: 192.0733.
(s, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
W. Xu et al.
Feature
Synthesis
5-Chloro-N,N-dimethylbenzo[d]thiazol-2-amine (3f)
6-Methyl-N,N-diethylbenzo[d]thiazol-2-amine (3k)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
Yield: 187 mg (88 %); pale-white solid; mp 108–110 °C.
Yield: 196 mg (89 %); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.46 (s, 1 H), 7.39 (d, J = 4.0 Hz, 1 H),
6.93 (s, 1 H), 3.12 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 169.54, 154.18, 131.88, 129.28,
121.20, 120.99, 118.69, 40.12.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 8.0 Hz, 1 H), 7.36 (s, 1 H),
7.06 (d, J = 8.4 Hz, 1 H), 3.56–3.51 (m, 4 H), 2.36 (s, 3 H), 1.27–1.23 (m,
6 H).
13C NMR (100 MHz, CDCl3): δ = 166.81, 150.91, 130.52, 130.40,
126.97, 120.64, 118.10, 45.34, 21.21, 12.91.
HRMS (ESI): m/z calcd for C9H9ClN2S: 212.0175; found: 212.0183.
HRMS (ESI): m/z calcd for C12H16N2S: 220.1034; found: 220.1045.
5-Methoxy-N,N-dimethylbenzo[d]thiazol-2-amine (3g)
6-Chloro-N,N-diethylbenzo[d]thiazol-2-amine (3l)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
Yield: 189 mg (91%); light-pink solid; mp 134–136 °C.
Yield: 202 mg (84%); light-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.40 (s, 1 H), 7.31 (d, J = 8.0 Hz, 1 H),
7.09 (d, J = 8.4 Hz, 1 H), 3.46–3.41 (m, 4 H), 1.16 (t, J = 7.2 Hz, 6 H).
1H NMR (400 MHz, CDCl3): δ = 7.67 (s, 1 H), 7.20 (d, J = 8.8 Hz, 1 H),
6.60 (d, J = 8.8 Hz, 1 H), 3.73 (s, 3 H), 3.32 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 180.74, 158.19, 137.11, 129.31,
117.99, 112.11, 111.26, 55.68, 41.33.
13C NMR (100 MHz, CDCl3): δ = 167.37, 151.78, 131.72, 126.16,
125.63, 120.13, 119.04, 45.48, 12.82.
HRMS (ESI): m/z calcd for C10H12N2OS: 208.0670; found: 208.0679.
HRMS (ESI): m/z calcd for C11H13ClN2S: 240.0488; found: 240.0498.
2-(Dimethylamino)benzo[d]thiazole-6-carbonitrile (3h)
5-Methyl-N,N-diethylbenzo[d]thiazol-2-amine (3m)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
Yield: 146 mg (72%); pale-brown solid; mp 160–162 °C.
Yield: 180 mg (82%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.73 (s, 1 H), 7.43 (s, 2 H), 3.16 (s, 6 H).
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 8.0 Hz, 1 H), 7.38 (s, 1 H),
6.85 (d, J = 8.0 Hz, 1 H), 3.55–3.50 (m, 4 H), 2.39 (s, 3 H), 1.27–1.23
(m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 170.90, 156.60, 131.68, 129.95,
124.69, 119.70, 118.74, 102.91, 40.30.
HRMS (ESI): m/z calcd for C10H9N3S: 203.0517; found: 203.0506.
13C NMR (100 MHz, CDCl3): δ = 167.60, 153.43, 135.70, 127.35,
121.99, 120.10, 120.10, 119.05, 45.41, 21.58, 12.92.
N,N-Diethylbenzo[d]thiazol-2-amine (3i)
HRMS (ESI): m/z calcd for C12H16N2S: 220.1034; found: 220.1022.
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
5-Chloro-N,N-diethylbenzo[d]thiazol-2-amine (3n)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
Yield: 177 mg (86 %); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.54 (t, J = 4.4 Hz, 2 H), 7.25 (t, J =
7.6 Hz, 1 H), 7.01 (t, J = 6.8 Hz, 1 H). 3.57–3.52 (m, 4 H), 1.26 (t, J =
7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 167.30, 130.24, 125.93, 120.88,
120.56, 118.45, 45.54, 12.87.
Yield: 209 mg (87%); light-yellow solid; mp 103–104 °C.
1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1 H), 7.24 (d, J = 6.4 Hz, 1 H),
7.02 (d, J = 8.4 Hz, 1 H), 3.77–3.72 (m, 4 H), 1.30 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 179.10, 137.48, 132.30, 129.67,
126.44, 125.62, 124.94, 45.82, 12.64.
HRMS (ESI): m/z calcd for C11H14N2S: 206.0878; found: 206.0864.
HRMS (ESI): m/z calcd for C11H13ClN2S: 240.0488; found: 240.0475.
6-Bromo-N,N-diethylbenzo[d]thiazol-2-amine (3j)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
5-Methoxy-N,N-diethylbenzo[d]thiazol-2-amine (3o)
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:1) to give the
target compound.
Yield: 236 mg (83%); very light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.63 (s, 1 H), 7.36–7.31 (m, 2 H), 3.54–
3.49 (m, 4 H), 1.24 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 179.35, 135.89, 131.50, 129.91,
128.47, 128.08, 117.99, 45.77, 12.67.
Yield: 215 mg (91%); light-yellow solid; mp 77–78 °C.
1H NMR (400 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.18 (d, J = 9.2 Hz, 1 H),
6.59 (d, J = 9.2 Hz, 1 H), 3.74 (s, 7 H), 1.28 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 179.13, 158.08, 137.14, 129.14,
117.80, 112.19, 111.29, 55.70, 45.74, 12.66.
HRMS (ESI): m/z calcd for C11H13BrN2S: 283.9983; found: 283.9992.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
W. Xu et al.
Feature
Synthesis
HRMS (ESI): m/z calcd for C12H16N2OS: 223.0983; found: 223.0975.
N,N-Dimethylthiazolo[5,4-b]pyridin-2-amine (3p)
(7) Kale, M.; Mene, D. Int. J. Pharma Bio Sci. 2013, 4, 503.
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Chankeshwara, S. V. Green Chem. 2007, 9, 1335.
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2004, 45, 2825.
According to the typical procedure, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to give the
target compound.
Yield: 161 mg (92%); yellow solid; mp 90–92 °C.
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 4.0 Hz, 1 H), 7.61 (d, J =
4.0 Hz, 1 H), 7.11–7.08 (m, 1 H), 3.01 (s, 6 H).
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3029.
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Lett. Rev. 2010, 3, 209.
13C NMR (100 MHz, CDCl3): δ = 167.46, 155.69, 147.37, 141.67,
124.26, 121.13, 39.74.
HRMS (ESI): m/z calcd for C8H9N3S: 179.0517; found: 179.0525.
(16) Moghaddam, F. M.; Ismaili, H.; Bardajee, G. R. Heteroat. Chem.
2006, 17, 136.
Funding Information
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62, 197.
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2201.
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2000, 41, 425.
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S. Tetrahedron Lett. 2003, 44, 6073.
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46, 4345.
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(26) Itoh, T.; Mase, T. Org. Lett. 2007, 9, 3687.
We thank the following for financial support: The National Natural
Science Foundation of China (21302150, 11405050), Hubei Provincial
Department of Education (D20131501), Scientific Research Founda-
tion for the Returned Overseas Chinese Scholars, State Education Min-
istry [2012]1707, President Foundation of Wuhan Institute of
Technology (2014038), the Foundation of Chutian Distinguished Fel-
low from Hubei Provincial Department of Education, and the Founda-
tion of High-End Talent Cultivation Program from Wuhan Institute of
Technology.
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Acknowledgment
We thank Prof. Aiwen Lei at Wuhan University for his generous NMR
analysis support.
(27) Downer-Riley, N. K.; Jackson, Y. A. Tetrahedron 2008, 64, 7741.
(28) (a) Muthusamy, S.; Paeamasivam, R.; Ramakrishnan, V. T. J. Het-
erocycl. Chem. 1991, 28, 759. (b) Wang, J.; Peng, F.; Jiang, Z. L.;
Wang, L.; Bai, J.; Pan, Y. Tetrahedron Lett. 2008, 49, 467.
(29) (a) Evinder, G.; Batey, R. A. Org. Lett. 2003, 5, 133. (b) Joyce, L. L.;
Batey, R. A. Org. Lett. 2009, 11, 2792. (c) Sharma, S.; Pathare, R.
S.; Maurya, A. K.; Gopal, K.; Roy, T. K.; Sawant, D. M.; Pardasani,
R. T. Org. Lett. 2016, 18, 356. (d) Sahoo, S. K.; Banerjee, A.;
Chakraborty, S.; Patel, B. K. ACS Catal. 2012, 2, 544. (e) Banerjee,
A.; Santra, S. K.; Rout, S. K.; Patel, B. K. Tetrahedron 2013, 69,
9096. (f) Wang, J. K.; Zong, Y. X.; Zhang, X. X.; Gao, Y.; Li, Z. L.;
Yue, G. R.; Quan, Z. J.; Wang, C. L. Synlett 2014, 25, 2143.
(30) (a) Guo, Y. J.; Tang, R. Y.; Zhong, P.; Li, J. H. Tetrahedron Lett.
2010, 51, 649. (b) Khatun, N.; Jamir, L.; Ganesh, M.; Patel, B. K.
RSC Adv. 2012, 2, 11557. (c) Xu, W.; Zeng, M. T.; Liu, M.; Liu, X.;
Chang, C. Z.; Zhu, H.; Li, Y. S.; Dong, Z. B. Chem. Lett. 2017, DOI:
10.1246/cl.170023.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588835.
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References and Notes
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(2) Yalchin, I.; Oren, I.; Sener, E.; Akin, A.; Ucaryurk, N. Eur. J. Med.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G