A Mild Synthesis of 2-Substituted Benzothiazoles via Nickel-Catalyzed Intramolecular Oxidative C-H Functionalization

Article abstract of DOI:10.1021/acs.joc.9b02543

A highly efficient synthetic method for the preparation of 2-aminobenzothiazoles starting from arylthioureas has been reported. By using a nickel catalyst, arylthioureas undergo intramolecular oxidative C-H bond functionalization, giving the desired 2-aminobenzothiazoles in good to excellent yields. This protocol features an inexpensive catalyst, low catalyst loading, mild reaction conditions, a short reaction time, and good to excellent yields, and it can be scaled up easily to a gram scale with almost no yields decreasing.

Full text of DOI:10.1021/acs.joc.9b02543

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Article
A Mild Synthesis of 2-Substituted Benzothiazoles via Nickel-
Catalyzed Intramolecular Oxidative C-H Functionalization
Ming-Yuan Gao, Jing-Hang Li, Shi-Bo Zhang, Li-Jun Chen, Yuesheng Li, and Zhi-Bing Dong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02543 • Publication Date (Web): 17 Dec 2019
Downloaded from pubs.acs.org on December 17, 2019
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A Mild Synthesis of 2-Substituted Benzothiazoles via
Nickel-Catalyzed
Intramolecular
Oxidative
C-H
Functionalization
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b+
b+
b
b
*a
Ming-Yuan Gao, Jing-Hang Li, Shi-Bo Zhang, Li-Jun Chen, Yue-Sheng Li and
Zhi-Bing Dong*a, b
aHubei Key Laboratory of Radiation Chemistry and Functional Materials, School of
Nuclear Technology and Chemistry & Biology, Hubei University of Science and
Technology, Xianning 437100, China.
bSchool of Chemistry and Environmental Engineering, Wuhan Institute of
Technology, Wuhan 430205, China.
+These authors contribute equally to this work
*Email: dzb04982@wit.edu.cn
*Email:frank78929@163.com
R2
H
N
NiBr2 (1 mol%)
R2
N
N
S
R3
PhI(OAc) (1 eq.)
2
R1
R1
N
S
Pyridine (2 eq.)
R3
H
1,4-dioxane
open air, r.t., 10min.
Nickel catalysis
Room temperature
Short reaction time
Low catalyst loading
Easily scaled-up
Mild reaction conditions
ABSTRACT
A highly-efficient synthetic method for the preparation of 2-aminobenzothiazoles
starting from arylthioureas has been reported. By using a nickel catalyst, arylthioureas
undergo intramolecular oxidative C-H bond functionalization, giving the desired
2
-aminobenzothiazoles in good to excellent yields. This protocol features inexpensive
catalyst, low catalyst loading, mild reaction conditions, short reaction time, good to
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excellent yields and can be scaled up easily to gram-scale with almost no yields
decreasing.
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INTRODUCTION
In the last few years, great achievements in synthetic chemistry have been made due
to the advances in the oxidative cross-coupling area. As a result, oxidative
cross-couplings have long been highly advocated, and one of these powerful
1
applications is C-H bond functionalization. First raw transition metal (Pd, Ru, etc.)
and non-first raw transition metal catalysts (Fe, Cu, etc.) have been widely used in
cross-coupling, while the reaction conditions are not mild enough and reaction
2
2
efficiency still needs improving. In oxidative cross coupling, the direct C(sp )−H
functionalization is particularly promising, primarily because construction of
intramolecular C-heteroatom (N, O and S etc.) bond can be achieved in a novel
3
approach. However, most methods involved relatively expensive metal catalysts, less
4
5
user-friendly strong oxidants or pre-activation designs, which not only bring large
amounts of residual metal impurities, but also render unnecessary process and costs.
Therefore, it would be quite attractive to explore more effective and mild conditions
2
for direct C(sp )−H functionalization. Nevertheless, there are only a few examples
where mild conditions are able to be applied to the construction of C-heteroatom
bonds.
Benzothiazole-related structures are widely existent in medical and agricultural
6
7
chemicals, bioactive natural products and organic optoelectronic materials. Thus,
organic chemists are devoted to achieve their synthesis mildly and effectively, and
choosing readily and commercially available N-arylthioureas as starting materials to
form 2-aminobenzo-thiazoles is widely accepted (Scheme 1). In 2008, Inamoto
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reported that the Pd-catalyzed strategy was suitable for the synthesis of
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-aminobenzothiazoles, Batey, Liu and Pardasani lately re-explored the reaction
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10a
conditions by using different transition metals such as Pd and Ru. However, all
these reactions used expensive transition metals as catalysts and required high
temperature and long reaction time. Thus, a milder and more effective way to access
the fast synthesis of 2-aminobenzothiazoles is highly desired.10b In 2012, Lei
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developed iron-promoted cyclization to furnish 2-aminobenzothiazoles, in which
only a few arylthioureas were chosen as substances. Though the iron catalysts have
the characteristics of low cost and easy availability, the yields of obtained
2-aminobenzo-thiazoles were not satisfactory.
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Scheme 1. Protocols for the Synthesis of 2-Aminobenzothiazoles
Traditional Synthetic Method
R
NH2
S
N
R
+
S
X
0
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0
(
X=Cl, Br, I)
R
N
H
N
ref 3
Pd/Cu
NH2
SH
R
Br
+
TMTD
S
2
ref 4
R
N
R
S
ref 5d
H
N
t
BuOK
Pd/Cu
N
NH2
R
RCOOH
RNCS
or
+
S
Br
SH
ref 5a-5c
ref 5e-5g
C-H Bond Functionalization
R
H
R
N
R
N
S
transition-matal catalyst
N
N
R
temperature, time
S
H
o
ref 8: PdCl -CuI , 100 C, 12h
2
o
ref 9a: Pd(PPh ) -MnO , 80 C, 4.5h
3
4
2
o
ref 9b: Pd(COD)Cl , 100 C, 12h
2
o
ref 9c: Pd(OAc) , 80 C, 4h
2
o
ref 10: RuCl , 100 C, 6h
3
o
ref 11: FeCl , 80 C, 4h
3
This work
R
N
R
H
N
S
R
R
N
N
H
N
R
R
Ni
N
S
S
room temp.
H
H
only a few minutes yields up to 95%
It is worthy to note that, nickel salts boast low cost and relative low toxicity (unlike
most expensive metal catalysts), and have been reported as powerful catalysts in the
1
2
cross-coupling reactions. To our best knowledge, there were almost no reports on
the nickel-catalyzed synthesis of 2-aminobenzothiazoles at mild conditions (eg. room
1
3
temperature, low loading, et. al). As a part of our continued efforts to explore
modified protocols for the C-S formation reactions, we report herein an efficient
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protocol for the preparation of 2-aminobenzothiazoles via nickel-catalyzed
intramolecular oxidative C-H functionalization, particularly with N-arylthioureas as
the starting substances.
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RESULTS AND DISCUSSION
N,N-dimethyl-N’-phenylthiourea 1a was chosen as the substrate for the model
reaction, aiming at fast and efficient nickel-catalyzed oxidative coupling (Table 1).
The reaction was performed in 1,4-dioxane by using 1 equiv. of PhI(OAc) (PIDA:
2
Phenyliodine(III) diacetate) as oxidant and 2 equiv. of pyridine as base, the target
product 2a could not be detected even after 6 hours (entry 1). Then 10 mol% NiCl2
was added as the catalyst in the system and it helped to furnish 2a in 28% isolated
yield (entry 2). Encouraged by this initial trial, other nickel catalysts including
(
dppp)NiCl , NiBr and Ni(OAc) were tested (entry 2-5) and results of the
2 2 2
experiments indicated that NiBr gained the best catalytic result in all studies (entry 4,
2
yield: 83%). Subsequently, various oxidants (entries 4, 6-8) were examined and it was
found that only PIDA could promote the reaction. The base screening (entries 4, 9-11)
and the solvent screening (entries 4, 12-14) revealed that pyridine was the optimal
base, and 1,4-dioxane was the most suitable solvent for the model reaction. To our
delight, by reducing the catalyst loading and shortening the reaction time, the reaction
could undergo smoothly even by adding 1 mol% equiv. of NiBr in 10 minutes (entry
2
16). Trace of 2-substituted benzothiazole was obtained when the amount of PIDA was
decreased to 50 mol% (entry 17). Thus, we believe that the PIDA is crucial for the
reaction, and the air might not be the co-oxidant in this reaction.
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Table 1. The Reaction Conditions Optimization a.
H
N
N
N
conditions
N
S
S
H
0
1
2
3
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5
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7
8
9
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1a
2a
b
Entry
Cat. (mol %)
-
Oxidant
PIDA
PIDA
PIDA
PIDA
PIDA
Base
Solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
Py
Py
Py
Py
Py
Py
Py
Py
360
90
90
90
90
90
90
90
90
90
90
90
90
90
90
10
trace
28
26
83
0
NiCl
(dppp)NiCl
NiBr (10)
Ni(OAc) (10)
NiBr
2
(10)
2
(10)
2
2
2
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
K
2
S
2
O
8
N.R.
0
NiBr
2
2
PIFA
DDQ
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
NiBr
0
NiBr
2
2
Cs
2
CO
3
0
1
1
1
1
1
1
1
0
1
2
3
4
5
6
NiBr
Et
3
N
0
NiBr
2
tBuOK
Py
0
NiBr
NiBr
NiBr
2
2
2
56
30
20
82
82
trace
Py
DMSO
DCM
Py
NiBr
2
(1)
(1)
(1)
Py
dioxane
dioxane
dioxane
NiBr
2
PIDA
Py
1
7c
NiBr
2
PIDA
Py
10
a
b
Reaction conditions: 1a (0.5 mmol), oxidant (1 eq.), base (2 eq.), room temperature, open air. Isolated yield.
cPIDA loading: 50 mol%.
After the optimized reaction conditions were obtained, the substrate generality to
furnish 2-dimethylamino-benzothiazoles 2 (Scheme 2) was explored. As shown in
Scheme 2, various substrates, whenever with electron withdrawing groups or electron
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donating groups, can be synthesized efficiently and rapidly. Initially, various
substituents on phenyl rings were tested. The phenylthioureas with halogen atoms in
the para-position (Scheme 2, 2b-2d) were smoothly transformed to the intended
products in excellent yields (86-83%), but the stronger electron-withdrawing groups,
such as nitro and cyano groups slightly and negatively influenced the yields (Scheme
1
1
1
1
1
1
1
1
1
1
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2
2
2
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9
0
2
, 2e-2f). Subsequently, the substrates with electron donating groups were explored
(Scheme 2, 2g-2i), and excellent yields were achieved (90-94%). Substrates
containing ortho halogens or nitro groups (Scheme 2, 2j-2m) were also compatible for
the reaction, giving the target cyclization products in moderate to good yields
(59-81%).
Scheme 2. Substrate Generality to Afford 2-Dimethylamino-benzothiazoles 2 a
H
N
NiBr (1 mol%)
2
N
PhI(OAc) (1 eq.)
N
S
2
R
N
R
Pyridine (2 eq.)
1,4-dioxane, r.t., 10min.
S
N
H
1
2
N
S
N
S
N
N
S
N
S
N
S
N
N
N
N
N
F
Cl
Br
O2N
2
a, 82%
2b, 86%
2c, 85%
2d, 83%
2e, 72%
Cl
N
S
N
S
N
S
N
S
N
S
N
N
N
N
N
N
NC
O
2
f, 68%
2g, 92%
2h, 90%
2i, 94%
NO2
2j, 74%
Cl
F
N
N
S
N
S
S
Cl
2l, 81%
2m, 62%
2k, 59%
aReaction conditions: 1 (0.5 mmol), open air, isolated yields.
Encouraged by above results, a series of N-substituted arylthioureas were explored
(Scheme 3). Firstly, 2-diethylamino-benzothiazole (Scheme 3, 4a) was furnished with
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2
2
2
2
2
2
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6
good yield (77%), and para-halogen substituted arylthioureas (Scheme 3, 4b-4d) were
also synthesized in good to excellent yields (76-84%). Stronger electron-withdrawing
groups, such as cyano or nitro (Scheme 3, 4g, 4h) decreased the yields of the product
0
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3
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(58-62%). In remarkable contrast, electron-donating groups (Scheme 3, 4e, 4f)
improved the yields (85-88%). Next, 2-N-containing heterocyclic benzothiazoles were
synthesized successfully (Scheme 3, 4i-4n), and we were pleased to find that they all
showed excellent yields (80-95%).
Scheme 3. Substrate Scope for N-substituted Arylthioureas a
R2
H
N
NiBr (1 mol%)
2
R2
N
PhI(OAc) (1 eq.)
N
S
R3
2
R1
N
R1
Pyridine (2 eq.)
1,4-dioxane, r.t. 10min.
R3
S
H
3
4
N
S
N
N
N
S
N
N
N
N
N
N
N
N
N
N
S
S
F
Cl
Br
4
a, 77%
4b, 79%
4c, 84%
4d, 76%
N
S
N
S
N
S
N
S
N
N
O
O
NC
O N
2
4
e, 85%
4f, 88%
4g, 58%
4h, 62%
N
S
N
S
N
S
N
S
O
O
N
N
O
O
Cl
O N
2
4i, 90%
4j, 95%
4k, 88%
4l, 80%
N
S
N
S
O
4m, 84%
4n, 80%
aReaction conditions: 1 (0.5 mmol), open air, isolated yield.
In organic synthesis (especially total synthesis), most natural products have elaborate
structures and sensitive functional groups, which means that the harsh reaction
conditions, such as strong oxidants or high temperatures should be avoid.14
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Furthermore, to access fast and promising preparations, organic chemists are devoted
to explore various approaches which could be extended to gram-scale production in
1
5
short time. To illustrate the easy performance and the potential application, we
scaled up the reaction in a gram-scale level at standard reaction conditions (room
temperature, within 15 minutes). Much to our excitement, the model reaction
proceeded quite well with very limited yield loss (around 5%, Scheme 4).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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9
0
1
2
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4
5
6
7
8
9
0
Scheme 4. Gram-scale Synthesis of 2-Dimethylamino-Benzothiazole.
H
N
NiBr2 (1 mol%)
N
N
S
PhI(OAc) (1 eq.)
2
N
S
Pyridine (2 eq.)
1,4-dioxane
H
6
1
mmol
.081 g
open air, r.t., 10min.
0.802 g
yield: 75%
In order to figure out the reaction mechanism, 1 equivalent of TEMPO and zinc
powder was added respectively in the control experiments. The results showed that
when TEMPO was added, the yield of the product did not decrease significantly,
indicating that this reaction does not proceed in a radical pathway. In contrast, when
zinc powder was added, the reaction was drastically suppressed, showing that an
oxidative step was involved. Besides, the reaction could also be carried out under a
nitrogen atmosphere. Based on above experimental results and previously reported
literatures,10,16 the reaction mechanism is proposed (Scheme 5). Firstly, arylthiourea B
is transformed to isothiourea under the action of pyridine and then complexed with
the Ni(II) catalyst A to form the intermediate C (pyridine might play the role as a
ligand to stabilize the intermediate C). Subsequently, a π-complex is formed through
Ni-centered electrophilic attacking the benzene, which is rapidly transformed to
σ-complex D. With the action of pyridine, D is deprotonated to give intermediate E,
which undergoes reductive elimination to give the intended molecule F along with Ni0
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
catalyst. Finally, the Ni catalyst is oxidized by PhI(OAc) to proceed the next
2
catalytic cycle.
Scheme 5. Control Experiments and Proposed Mechanism.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NiBr (1 mol%)
2
H
N
PhI(OAc) (1 eq.)
N
N
2
N
Additive (1 eq.)
Pyridine (2 eq.)
S
S
1,4-dioxane, r.t. 10min.
TEMPO, Yield: 71%
Zn, Yield: 0%
Additive:
NiBr (1 mol%)
2
H
N
PhI(OAc) (1 eq.)
N
N
S
N
2
Pyridine (2 eq.), N2
,4-dioxane, r.t. 10min.
S
1
Yield: 81%
H
N
N
-
PhI + 2 OAc
S
PhI(OAc)
2
B
II
+
Ni X L
m
n
-
2X
A
Py
N
S
X-
+
N
X=halogen
N
0
Ni Xm-2L
n
H
F
N
N
N
S
NiII
N
Xm-1
II S
Ni
E
Xm-2
Ln
Ln
C
H
N
N
H
+
N
X-
II S
Py
Ni
Xm-2
Ln
D
CONCLUSION
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In summary, we introduce here an efficient and mild protocol for the easy synthesis of
2
-substituted benzothiazoles. By using readily available arylthioureas as starting
materials and NiBr as catalyst, the target 2-substituted benzothiazoles could be
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
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4
5
6
7
8
9
0
synthesized in good to excellent yields. Compared with former methods, this reaction
features lower cost, easier performance and shorter time. Furthermore, the reaction
can be scaled up easily with almost no yield loss, illustrating its potential values in
pharmaceutical and industrial production.
EXPERIMENTAL SECTION
General Information
In terms of the starting materials (arylthiourea derivatives), 1k (to give 2k), 3m (to
give 4m) and 3a (to give 4a) are all commercially available, the rest arylthioureas are
obtained according to ref. 17. Flash column chromatography was operated on silica
gel with petroleum ether-EtOAc (PE-EA) as the eluent. Thin layer Chromatography
was adopted and visualized under UV light. The RY-1G instrument was adopted to
determine melting points of target compounds. The HRMS (high-resolution mass
spectra) was recorded from a Finnigan MAT 95Q mass instrument (ESI). A Bruker
AM400 NMR instrument was operated in CDCl to record NMR spectra.
3
Typical procedure for the synthesis of 2-substitutedbenzothiazole 2 or 4
Arylthiourea derivative 1 or 3 (0.5 mmol), PhI(OAc) (PIDA) (1eq., 0.5 mmol,
2
0
.1611g), NiBr (1mol%, 0.005 mmol, 0.0011g), 1,4-dioxane (2.5 mL) were mixed in
2
a dried tube with a magnetic stirring bar (open to air), and then pyridine (2eq., 1.0
o
mmol) was added. The reaction was conducted at 25 C and detected by TLC. After
the reaction was finished, it was then quenched with water and extracted with ethyl
acetate. The preliminary solution was dried over Na SO and evaporated. The crude
2
4
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5
6
material was further purified by column chromatography to get the intended product 2
or 4.
Data of the products
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N,N-dimethylbenzo[d]thiazol-2-amine (2a)17b
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2a as a yellow crystal (73 mg, yield =
o
1
8
2%). mp: 83-85 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 7.56 (t, 2H, J = 8.0 Hz), 7.27 (t, 1H, J = 8.0 Hz), 7.03 (t, 1H, J = 8.0 Hz), 3.17
1
3
(
s, 6H). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 168.1,
3
+
152.4,130.4, 125.4, 120.3, 120.0, 118.1, 39.6. HRMS (ESI) m/z [M+H] Calcd for
C H N S (179.0638), found: 179.0640.
9
11
2
6
-fluoro-N,N-dimethylbenzo[d]thiazol-2-amine (2b)17b
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2b as a white solid (84 mg, yield = 86%).
o
1
mp: 116-118 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
1
3
7
.54-7.51 (m, 1H), 7.33 (d, 1H, J=8.0 Hz), 7.05 (t, 1H, J = 8.0 Hz), 3.16 (s, 6H). C
NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 167.4, 157.0 (d, J =
3
2
38.0 Hz), 148.4, 130.6 (d, J = 11.0 Hz), 118.1 (d, J = 9.0 Hz), 112.7 (d, J = 23.0 Hz),
+
1
06.5 (d, J = 27.0 Hz), 39.3. HRMS (ESI) m/z [M+H] Calcd for C H FN S
9
10
2
(197.0543), found: 197.0541.
-chloro-N,N-dimethylbenzo[d]thiazol-2-amine (2c)17b
6
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2c as a brown crystals (90 mg, yield =
o
1
8
6%). mp: 102-103 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 7.50 (s, 1H), 7.42 (d, 1H, J = 12.0 Hz), 7.20 (d, 1H, J = 8.0 Hz), 3.15 (s, 6H).
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13C NMR (100 MHz, in CDCl3 with TMS as inner standard): δ (ppm) 167.7, 150.5,
+
1
31.0, 125.2, 124.8, 119.1, 118.2, 39.0. HRMS (ESI) m/z [M+H] Calcd for
C H ClN S (213.0248), found: 213.0248.
9
10
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-bromo-N,N-dimethylbenzo[d]thiazol-2-amine (2d)17b
6
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2d as a yellow solid (106 mg, yield =
o
1
8
3%). mp: 109-111 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 7.68 (d, 1H, J = 1.0 Hz), 7.42 (d, 1H, J = 8.0 Hz), 7.38-7.36 (m, 1H), 3.20 (s,
1
3
6
H). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 167.6,
3
+
150.6, 131.3, 128.0, 121.9, 118.6, 112.1, 39.1. HRMS (ESI) m/z [M+H] Calcd for
C H BrN S (256.9743), found: 256.9739.
9
10
2
N,N-dimethyl-6-nitrobenzo[d]thiazol-2-amine (2e)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 1:1) to afford 2e as a bright yellow solid (80 mg, yield =
o
1
7
2%). mp: 196-199 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 8.44 (s, 1H), 8.14 (d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 12.0 Hz), 3.23 (s, 6H).
1
3
C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 171.8, 158.1,
3
+
1
41.1, 131.0, 122.4, 117.5, 117.0, 40.2. HRMS (ESI) m/z [M+H] Calcd for
C H N O S (224.0488), found: 224.0491.
9
10
3
2
2-(dimethylamino)benzo[d]thiazole-6-carbonitrile (2f)17b
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 2:1) to afford 2f as a grey solid (69 mg, yield = 68%).
o
1
mp: 158-160 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
13
7
.78 (s, 1H), 7.47 (s, 2H), 3.19 (s, 6H). C NMR (100 MHz, in CDCl with TMS as
3
inner standard): δ (ppm) 170.9, 156.5, 131.6, 130.0, 124.7, 119.7, 118.7, 103.1, 40.3.
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2
2
2
2
2
2
2
2
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3
3
3
3
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3
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4
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4
4
4
4
4
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5
5
5
5
5
5
5
6
+
HRMS (ESI) m/z [M+H] Calcd for C H N S (204.0590), found: 204.0595.
1
0
10
3
6
-methyl-N,N-dimethylbenzo[d]thiazol-2-amine (2g)17b
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2g as a red-brown solid (88 mg, yield =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
9
2%). mp: 100-101 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(
ppm) 7.43 (d, 1H, J = 8.0 Hz), 7.10 (d, 1H, J = 4.0 Hz), 6.86-6.84 (m, 1H), 3.76 (s,
1
3
3
H), 3.10 (s, 6H). C NMR (100 MHz, in CDCl with TMS as inner standard): δ
3
(
ppm) 166.0, 148.7, 128.8, 128.4, 124.9, 118.5, 116.1, 37.9, 19.0. HRMS (ESI) m/z
+
[
M+H] Calcd for C H N S (193.0794), found: 193.0791.
10 13
2
6-methoxy-N,N-dimethylbenzo[d]thiazol-2-amine (2h)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2h as a light yellow solid (93 mg, yield =
o
1
90%). mp: 89-91 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(
ppm) 7.43 (d, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 1.0 Hz), 6.86-6.83 (m, 1H), 3.75 (s,
1
3
3
H), 3.10 (s, 6H). C NMR (100 MHz, in CDCl with TMS as inner standard): δ
3
(
ppm) 167.4, 154.6, 147.2, 131.8, 119.0, 113.4, 105.2, 55.8, 40.2. HRMS (ESI) m/z
+
[
M+H] Calcd for C H N OS (209.0743), found: 209.0742.
1
0
13
2
4
-methyl-N,N-dimethylbenzo[d]thiazol-2-amine (2i)19
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2i as a white solid (91 mg, yield = 94%).
o
1
mp: 50-52 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
7
.35 (d, 1H, J = 8.0 Hz), 7.01 (d, 1H, J = 8.0 Hz), 6.87 (t, 1H, J = 8.0 Hz), 3.09 (s,
1
3
6H), 2.49 (s, 3H). C NMR (100 MHz, in CDCl with TMS as inner standard): δ
3
(
ppm) 166.7, 151.1, 129.7, 127.4, 125.4, 119.5, 116.8, 38.8, 17.1. HRMS (ESI) m/z
+
[
M+H] Calcd for C H N S (193.0794), found: 193.0795.
1
0
13
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4
-chloro-N,N-dimethylbenzo[d]thiazol-2-amine (2j)
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2j as a white solid (78 mg, yield = 74%).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
mp: 95-97 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
7
6
1
.27 (d, 1H, J = 8.0 Hz), 7.12 (d, 1H, J = 8.0 Hz), 6.76 (t, 1H, J = 8.0 Hz), 2.98 (s,
1
3
H). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 165.6,
3
+
47.0, 129.1, 122.9, 119.7, 115.9, 36.9. HRMS (ESI) m/z [M+H] Calcd for
C H ClN S (213.0248), found: 213.0244.
9
10
2
4
,6-dichloro-N,N-dimethylbenzo[d]thiazol-2-amine (2k)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 3:1) to afford 2k as a white solid (72 mg, yield = 59%).
o
1
mp: 116-118 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
1
3
7.43 (d, 1H, J = 4.0 Hz), 7.30 (d, 1H, J = 4.0 Hz), 3.20 (s, 6H). C NMR (100 MHz,
in CDCl with TMS as inner standard): δ (ppm) 166.7, 147.0, 130.9, 124.2, 123.5,
3
+
1
21.2, 116.8, 38.1. HRMS (ESI) m/z [M+H] Calcd for C H Cl N S (246.9858),
9
9
2
2
found: 246.9853.
4
-fluoro-N,N-dimethylbenzo[d]thiazol-2-amine (2l)
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 2l as a white crystals (76 mg, yield =
o
1
81%). mp: 86-88 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
13
(ppm) 7.25 (d, 1H, J = 8.0 Hz), 6.95-6.85 (m, 2H), 3.11 (s, 6H). C NMR (100 MHz,
in CDCl with TMS as inner standard): δ (ppm) 167.7, 152.1 (d, J = 248.0 Hz), 140.6
3
(d, J = 13.0 Hz), 132.7 (d, J = 5.0 Hz), 120.0 (d, J = 7.0 Hz), 115.3 (d, J = 4.0 Hz),
+
1
10.0 (d, J = 9.0 Hz), 39.2. HRMS (ESI) m/z [M+H] Calcd for C H FN S
9
10
2
(197.0543), found: 197.0546.
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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N,N-dimethyl-4-nitrobenzo[d]thiazol-2-amine (2m)
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 3:1) to afford 2m as a dark yellow solid (69 mg, yield =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
6
2%). mp: 189-191 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 7.98 (d, 1H, J = 8.0 Hz), 7.74 (d, 1H, J = 8.0 Hz), 7.02 (t, J = 8.0 Hz), 3.24 (s,
1
3
6
1
H). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 169.6,
3
+
45.7, 137.1, 133.6, 124.3, 121.0, 117.9, 38.8. HRMS (ESI) m/z [M+H] Calcd for
C H N O S (224.0488), found: 224.0482.
9
10
3
2
N,N-diethylbenzo[d]thiazol-2-amine (4a)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 7:1) to afford 4a as a light yellow oil (79 mg, yield =
1
7
7%). H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.42 (t,
3
2H, J = 8.0 Hz), 7.13 (t, 1H, J = 8.0 Hz), 6.89 (t, 1H, J = 8.0 Hz), 3.45-3.39 (m, 4H),
13
1
.13 (t, 6H, J = 8.0 Hz). C NMR (100 MHz, in CDCl with TMS as inner standard):
3
δ (ppm) 173.0, 159.0, 136.4, 131.5, 126.4, 126.2, 124.2, 51.1, 18.6. HRMS (ESI) m/z
+
[
M+H] Calcd for C H N S (207.0951), found: 207.0956.
11 15
2
6
-fluoro-N,N-diethylbenzo[d]thiazol-2-amine (4b)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 7:1) to afford 4b as a yellow oil (88 mg, yield = 79%).
1
H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.36-7.33 (m,
3
1
H), 7.18 (d, 1H, J = 8.0 Hz), 6.89 (t, 1H, J = 8.0 Hz), 3.47-3.41 (m, 4H), 1.17 (t, 6H,
1
3
J = 8.0 Hz). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
165.9, 156.7 (d, J = 257.0 Hz), 148.8, 130.3 (d, J = 10.0 Hz), 117.8 (d, J = 9.0 Hz),
+
1
12.3 (d, J = 23 Hz), 106.3 (d, J = 27 Hz), 44.4, 11.8. HRMS (ESI) m/z [M+H] Calcd
for C H FN S (225.0856), found: 225.0850.
1
1
14
2
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-chloro-N,N-diethylbenzo[d]thiazol-2-amine (4c)18
6
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 7:1) to give 4c as a yellow oil (100 mg, yield = 84%).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
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0
1
2
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0
1
2
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0
1
2
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7
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.40 (s, 1H),
3
7
6
1
.31 (d, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.0 Hz), 3.46-3.40 (m, 4H), 1.16 (t, 6H, J =
1
3
.0 Hz). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 165.8,
3
+
50.2, 130.1, 124.6, 124.0, 118.5, 117.4, 43.9, 11.2. HRMS (ESI) m/z [M+H] Calcd
for C H ClN S (241.0561), found: 241.0558.
1
1
14
2
6
-bromo-N,N-diethylbenzo[d]thiazol-2-amine (4d)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 7:1) to afford 4d as a yellow oil (107 mg, yield = 76%).
1
H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.63 (s, 1H),
3
1
3
7.36-7.30 (m, 2H), 3.54-3.49 (m, 4H), 1.24 (t, 6H, J = 6.0 Hz). C NMR (100 MHz,
in CDCl with TMS as inner standard): δ (ppm) 165.4, 150.1, 130.2, 127.0, 120.9,
3
+
1
17.5, 110.9, 43.5, 10.8. HRMS (ESI) m/z [M+H] Calcd for C H BrN S
1
1
14
2
(
285.0056), found: 285.0054.
N,N-diethyl-6-methylbenzo[d]thiazol-2-amine (4e)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 7:1) to afford 4e as a colorless oil (93 mg, yield = 85%).
1
H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.31 (d, 1H, J =
3
8
.0 Hz), 7.24 (s, 1H), 6.95 (d, 1H, J = 8.0 Hz), 3.44-3.39 (m, 4H), 2.25 (s, 3H), 1.13
1
3
(
t, 6H, J = 6.0 Hz). C NMR (100 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 166.8, 150.9, 130.5, 130.4, 126.9, 120.6, 118.1, 45.3, 21.2, 12.9. HRMS (ESI)
+
m/z [M+H] Calcd for C H N S (221.1107), found: 221.1103.
1
2
17
2
N,N-diethyl-6-methoxybenzo[d]thiazol-2-amine (4f)18
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6
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 7:1) to afford 4f as a yellow oil (103 mg, yield = 88%).
1
H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.43 (d, 1H, J =
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
.0 Hz), 7.12 (s, 1H), 6.88-6.85 (m, 1H), 3.79 (s, 3H), 3.55-3.50 (m, 4H), 1.26 (t, 6H,
1
3
J = 8.0 Hz). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
1
65.9, 154.5, 147.5, 131.4, 118.8, 113.2, 105.2, 55.9, 45.2, 12.8. HRMS (ESI) m/z
+
[
M+H] Calcd for C H N OS (237.1056), found: 237.1057.
1
2
17
2
2
-(diethylamino)benzo[d]thiazole-6-carbonitrile (4g)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 4g as a bright yellow oil (67 mg, yield =
1
5
1
8%). H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.81 (s,
3
1
3
H), 7.49 (s, 2H), 3.61-3.56 (m, 4H), 1.30 (t, 6H, J = 6.0 Hz). C NMR (100 MHz, in
CDCl with TMS as inner standard): δ (ppm) 168.9, 156.0, 130.5, 129.2, 123.8, 119.0,
3
+
1
17.8, 102.2, 45.1, 12.3. HRMS (ESI) m/z [M+H] Calcd for C H N S (232.0903),
1
2
14
3
found: 232.0900.
N,N-diethyl-6-nitrobenzo[d]thiazol-2-amine (4h)18
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 4h as a pale-yellow oil (67 mg, yield =
1
6
2%). H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 8.41 (d,
3
1H, J = 4.0 Hz), 8.12-8.09 (m, 1H), 7.41 (d, 1H, J = 12.0 Hz), 3.55 (d, 4H, J = 8.0
13
Hz), 1.25 (t, 6H, J = 8.0 Hz). C NMR (100 MHz, in CDCl with TMS as inner
3
standard): δ (ppm) 169.7, 157.6, 140.2, 129.9, 121.4, 116.5, 116.0, 45.0, 11.7. HRMS
+
(ESI) m/z [M+H] Calcd for C H N O S (252.0801), found: 252.0799.
1
1
14
3
2
-(benzo[d]thiazol-2-yl)morpholine (4i)20
4
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
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isolated by column (PE/EA = 5:1) to afford 4i as a white crystals (99 mg, yield =
o
1
9
0%). mp: 118-120 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 7.62-7.57 (m, 2H), 7.31 (t, 1H, J = 8.0 Hz), 7.10 (t, 1H, J = 8.0 Hz), 3.83 (t,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
4
H, J = 12.0 Hz), 3.62 (t, 4H, J = 8.0 Hz). C NMR (100 MHz, in CDCl with TMS
3
as inner standard): δ (ppm) 167.8, 151.2, 129.3, 124.9, 120.5, 119.5, 118.0, 65.0, 47.2.
+
HRMS (ESI) m/z [M+H] Calcd for C H N OS (221.0743), found: 221.0743.
11 13
2
4
-(6-methoxybenzo[d]thiazol-2-yl)morpholine (4j)20
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 4j as a white crystals (118 mg, yield =
o
1
95%). mp: 108-110 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 7.40 (d, 1H, J = 8.0 Hz), 7.08 (d, 1H, J = 4.0 Hz), 6.85-6.82 (m, 1H), 3.74 (t,
1
3
7
H, J = 8.0 Hz), 3.49 (t, 4H, J = 4.0 Hz). C NMR (100 MHz, in CDCl with TMS as
3
inner standard): δ (ppm) 166.6, 154.2, 145.6, 130.6, 118.8, 112.8, 104.2, 65.2, 54.8,
+
4
7.5. HRMS (ESI) m/z [M+H] Calcd for C H N O S (251.0849), found: 251.0850.
1
2
15
2
2
4
-(6-chlorobenzo[d]thiazol-2-yl)morpholine (4k)20
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 4k as a white crystals (111 mg, yield =
o
1
8
8%). mp: 121-123 C. H NMR (400 MHz, in CDCl with TMS as inner standard): δ
3
(ppm) 7.48 (d, 1H, J = 1.0 Hz), 7.37 (d, 1H, J = 8.0 Hz), 7.18-7.16 (m, 1H), 3.74 (t,
1
3
4H, J = 12.0 Hz), 3.51 (t, 4H, J = 12.0 Hz). C NMR (100 MHz, in CDCl with TMS
3
as inner standard): δ (ppm) 167.8, 149.9, 130.5, 125.5, 125.3, 119.2, 118.7, 64.9, 47.2.
+
HRMS (ESI) m/z [M+H] Calcd for C H ClN OS (255.0354), found: 255.0352.
1
1
12
2
4-(6-nitrobenzo[d]thiazol-2-yl)morpholine (4l)20
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 1:1) to afford 4l as a bright yellow solid (106 mg, yield
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
=
80%). mp: 185-187 C. H NMR (400 MHz, in CDCl with TMS as inner standard):
3
δ (ppm) 8.52 (d, 1H, J = 4.0 Hz), 8.22-8.19 (m, 1H), 7.52 (d, 1H, J = 8.0 Hz), 3.85 (t,
1
3
4H, J = 4.0 Hz), 3.71 (t, 4H, J = 4.0 Hz). C NMR (100 MHz, in CDCl with TMS as
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
inner standard): δ (ppm) 171.0, 156.8, 140.9, 129.7, 121.6, 117.4, 116.3, 65.1, 47.6.
+
HRMS (ESI) m/z [M+H] Calcd for C H N O S (266.0594), found: 266.0590.
1
1
12
3
3
2
-(2-methylpiperidin-1-yl)benzo[d]thiazole (4m)
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 4m as a colorless oil (97 mg, yield =
1
8
4%). H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.49-7.43
3
(m, 2H), 7.18 (t, 1H, J = 8.0 Hz), 6.94 (t, 1H, J = 8.0 Hz), 4.30 (t, 1H, J = 8.0 Hz),
3
.92-3.88 (m, 1H), 3.16-3.09 (m, 1H), 1.75-1.51 (m, 6H), 1.19 (d, 3H, J = 8.0 Hz).
1
3
C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm) 167.6, 151.9,
3
129.4, 124.8, 119.9, 119.5, 117.7, 51.0, 42.8, 29.1, 24.4, 17.7, 13.7. HRMS (ESI) m/z
+
[
M+H] Calcd for C H N S (233.1107), found: 233.1110.
1
3
17
2
6
-methoxy-2-(2-methylpiperidin-1-yl)benzo[d]thiazole (4n)
Based on THE ABOVE MENTIONED PROCEDURE, the crude material was
isolated by column (PE/EA = 5:1) to afford 4n as a colorless oil (104 mg, yield =
1
8
0%). H NMR (400 MHz, in CDCl with TMS as inner standard): δ (ppm) 7.35 (d,
3
1
H, J = 8.0 Hz), 7.05 (d, 1H, J = 1.0 Hz), 6.81-6.78 (m, 1H), 4.28-4.22 (m, 1H),
3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.15-3.08 (m, 1H), 1.76-1.52 (m, 6H), 1.19 (d, 3H, J
13
=
8.0 Hz). C NMR (100 MHz, in CDCl with TMS as inner standard): δ (ppm)
3
1
66.1, 153.4, 145.9, 130.1, 117.8, 112.1, 104.0, 54.7, 50.7, 42.5, 28.8, 24.2, 17.5,
+
13.3. HRMS (ESI) m/z [M+H] Calcd for C H N OS (263.1213), found: 263.1214.
1
4
19
2
1
13
Supporting Information: list of H and C NMR of products.
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ACKNOWLEDGMENT
The financial support from Hubei Key Laboratory of Radiation Chemistry and
Functional Materials, Hubei University of Science & Technology (2019-20KZ01),
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic
Functional Molecules, Hubei University (KLSAOFM1810), Hubei Provincial Science
and Technology (2019CFB596) are all greatly appreciated.
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Nazreen, S.; Haider, S. Synthesis and Evaluation of Pyrazolines Bearing
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(
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