Alkylation reactions of benzothiazoles with N,N-dimethylamides catalyzed by the two-component system under visible light

Article abstract of DOI:10.1016/j.tetlet.2018.12.064

Eosin Y/K₂S₂O₈ catalyzed C2-alkylation reactions of benzothiazoles with N,N-dimethylamides under visible light have been developed. The reactions completed smoothly in the presence of Eosin Y as the photocatalyst and K

Full text of DOI:10.1016/j.tetlet.2018.12.064

Accepted Manuscript
Alkylation Reactions of Benzothiazoles with N,N-dimethylamides catalyzed by
the Two-Component System under Visible Light
Jian-Quan Weng, Wen-Xiu Xu, Xiao-Qiang Dai, Jun-Hui Zhang, Xing-Hai Liu
PII:
S0040-4039(18)31522-3
https://doi.org/10.1016/j.tetlet.2018.12.064
TETL 50527
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 October 2018
19 December 2018
26 December 2018
Please cite this article as: Weng, J-Q., Xu, W-X., Dai, X-Q., Zhang, J-H., Liu, X-H., Alkylation Reactions of
Benzothiazoles with N,N-dimethylamides catalyzed by the Two-Component System under Visible Light,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.064
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Tetrahedron Letters
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Alkylation Reactions of Benzothiazoles with N,N-dimethylamides catalyzed by the
Two-Component System under Visible Light
Jian-Quan Weng*, Wen-Xiu Xu, Xiao-Qiang Dai, Jun-Hui Zhang, Xing-Hai Liu
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Eosin Y/K
visible light have been developed. The reactions completed smoothly in the presence of Eosin Y as the
photocatalyst and K as the oxidant under solvent-free conditions in open air. This green and
simple method provides an alternative route for the synthesis of C2-alkylation of benzothiazoles and
tolerates a number of functional groups to afford moderate to excellent yields.
2 2 8
S O catalyzed C2-alkylation reactions of benzothiazoles with N,N-dimethylamides under
2 2 8
S O
Available online
Keywords:
Visible light
Alkylation
2018 Elsevier Ltd. All rights reserved.
Benzothiazoles
N,N-dimethylamides
Eosin Y
2 2 8
K S O
Introduction
Previous works:
C2-substituted benzothiazole derivatives have attracted
1
great synthetic interests due to their broad biological
a) Weaver's work (2013)
2
properties. Amongst them, the structure of a benzothiazole
N
S
N
S
H
R1
Ir(ppy)3, imidazole
R1
attaching to an amide is also a building block of bioactive
Cl +
N
N
MeCN
3
4
compounds, such as herbicide, antivirulence drugs, androgen
Blue LED's, r.t.
5
6
receptor antagonists, dipeptidyl Peptidase IV Inhibitors (Fig. 1).
Great efforts have been devoted to preparing C2-substituted
benzothiazole derivatives.7 From the perspective of synthetic
simplicity and atom economy, the construction of C2-substituted
benzothiazole frameworks has focused on direct oxidative
39-93% yields
N
b) Shah's work (2016)
N
S
O
K2S2O8, H2O
27 W CFL,
R1
R1
+
S
r.t.
O
22-61% yields
8
9
coupling reactions with aromatic aldehydes, benzylamines,
c) Zhu's work (2016)
N
R
O
1
0
11
phenylglycine
derivatives,
diaryliodonium
salts,
O
1
2
K2S2O8
N
S
N
dicumylperoxides, methylarenes and cycloalkanes, as well as
R1
N
R
+
R1
1
3,14
S
70 ℃
amides.
Although advances have been achieved, still there
are some disadvantages, such as requirements of transition-metal
catalysts, strong bases, poisonous addictives, or high
temperature.
51-82% yields
This work (Two-Component System Photocatalysis)
1
5
O
N
S
Eosin Y, K2S2O8
5 W LED, r.t.
S
R1
R2
R1
O
+
N
1
N
N
O
N
S
N
R2
HO
N
Cl
58-88% yields
N
1
O
R = H, 5-Cl, 6-OMe, 4-Me, 6-Me,
6-CN, 5-Ac, 6-Ph
S
O
N
N
NH
R2 = H, Me, Et
O
O
visible light-mediated
solvent free
herbicide
antivirulence drugs
room temperature
S
N
Scheme 1. Methods for the preparation of C2-alkylation of
benzothiazoles
N
O
O
N
N
S
O
F3C
NC
N
16
N
Over the years, the visible light-promoted reactions have
N
N
O
H2N
emerged as powerful tools in organic synthesis17 owing to
abundant solar energy, convenient reaction devices and novel
reaction mechanisms. Amongst them, there is likewise a
growing trend of introducing photocatalysis into alkylation
reactions of benzothiazoles in recent years. In 2013, Weaver and
androgen receptor antagonists
dipeptidyl Peptidase IV Inhibitors
Fig. 1. Pharmaceuticals containing the structure of C2-
amidoalkylation of benzothiazole
18

2
Tetrahedron Letters
co-workers developed a visible light-induced and tris-fac-
Ir(ppy) catalyzed C2-alkylation of 2-chlorobenzothiazole
derivatives with tertiary aliphatic amines at room temperature
benzothiazoles with ethers employing potassium persulfate as
2
1
3
the catalyst at room temperature (Scheme 1b). Herein, we
report an efficient two-component photocatalytic system
1
9
(
Scheme 1a). However, the high cost, complex handling
2 2 8
comprising of Eosin Y/K S O for C2-alkylation reactions of
procedures, potential toxicity and limited availability of Ru/Ir
complexes in the future are disadvantages of these transition
metal-based methods,20 as stated earlier. In 2016, Shah et al.
developed the visible light-induced C2-alkylation of
benzothiazoles with N,N-dimethylamides under visible light. It’s
notable that, compared to the previous work of Zhu group
14
(Scheme 1c), our protocol works with the advantages of milder
conditions and higher yields in some cases.
Results and discussion
Table 1. Optimization of Reaction Conditions a
O
N
O
N
N
Photocatalyst
+
N
O
H
+
S
H
oxidant, solvent
S
S
N
N
15 W LED, r.t.
1a
2a
4a
3a
entry
catalyst (mol %)
Eosin B (1.0)
Eosin Y (1.0)
Rhodamine B (1.0)
Rose Bengal (1.0)
Eosin Y (1.0)
Eosin Y (1.0)
Eosin Y (1.0)
--
oxidant (eq.)
solvent
yield(3a:4a, %) b
trace
19:4
1
2
3
4
5
6
7
8
9c
--
--
--
--
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
10:0
15:3
K
2
S
2
O
8
(3)
(3)
45:20
22:3
Na
(NH
2 2 8
S O
4
)
2
S
2
O
8
(3)
12:3
K
2
K
2
K
2
K
2
K
2
K
2
S
2
S
2
S
2
S
2
S
2
S
2
O
O
O
O
O
8
8
8
8
8
(3)
20:6
Eosin Y (1.0)
Eosin Y (1.0)
Eosin Y (1.0)
Eosin Y (1.0)
Eosin Y (1.0)
(3)
(3)
(3)
(3)
(3)
44:16
26:4
1
1
1
1
1
1
0c
1c
2c
3c
4c
5c
C
2
H
5
OH
CN
CH
3
25:5
CHCl
3
28:6
O
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
68:12
n.d.
4CzIPN
9-mesityl-10-methylacridinium perchlorate
n.d.
1
6c,d
Eosin Y (1.0)
Eosin Y (0.5)
Eosin Y (1.5)
Eosin Y (2.0)
Eosin Y (3.0)
Eosin Y (5.0)
Eosin Y (1.0)
Eosin Y (1.0)
Eosin Y (1.0)
Eosin Y (1.0)
--
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
O
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
8
(3)
(3)
(3)
(3)
(3)
(3)
(2)
(4)
(5)
65:10
58:8
1
7c
8c
9c
0c
1c
2c
3c
4c
5c
6c
7e
1
65:10
62:10
55:12
54:9
1
2
2
2
2
2
2
2
2
63:10
67:10
65:10
24:5
--
K
K
K
2
2
2
S
S
S
2
O
O
O
8
8
8
(3)
(3)
(3)
29:9
Eosin Y (1.0)
Eosin Y (1.0)
2
2
31:2
2
8f
28:7
a
Reaction condition: 1a (0.5 mmol), 2a (3.0 equiv, 1.5 mmol), oxidant (3.0 equiv), photocatalyst (0.005 mmol, 1.0 mol%), solvent (5
b
c
d
e
mL), open to the air, at room temperature, 15 W Blue LED (λ= 450 nm), 48 h. Isolated yield. For 24 h. anhydrous DMF. Degassed
with N . in the dark.
2
f
In our initial studies, the reaction of benzothiazole (1a, 0.5 mmol) with an excess amount of N,N-dimethylformamide (2a, 1.5
mmol) was chosen as a model to optimize the reaction conditions. The results showed that Eosin Y was an effective photocatalyst for
this transformation, which afforded the target alkylation product of benzothiazole (3a) in 19% yield and the acylation product of
benzothiazole (4a) in 4% yield with irradiation by a 15 W blue light-emitting diode (LED) at room temperature under air atmosphere
after 48 hours (Table 1, entries 1-4). Inspired by previously reported C2-alkylation reactions of benzothiazoles utilizing persulfates as

oxidant,21,22 three kinds of common persulfates (Na
we found that the reaction proceeded smoothly in the presence of persulfates, and K
a in 45% yield (Table 1, entries 5-7). To ensure the significance of the catalyst, a control experiment was carried out without the
) were tried in the reactions, respectively. Delightfully,
resulted in better conversion which afforded
2 2 8 4 2 2 8 2 2 8
S O , (NH ) S O , K S O
2 2 8
S O
3
photocatalyst, and a lower yield (20%) of the product was observed as expected (Table 1, entry 8). Encouraged by this promising result,
we tried to shorten the reaction time to 24 h, the yield of 3a did almost not changed (Table 1, entry 9). Next, we surveyed a range of
2 5 3 3
solvents, the results indicated that C H OH, CH CN and CHCl were inferior to DMF (Table 1, entries 10−13). The better yield in
DMF was highly probably given by the reaction equilibrium driven by a lot excess of amides. And it was reported that Eosin Y was
2
3
2
subjected to tautomeric/protolytic equilibria and EYH was an effective photoredox catalyst only if the base was added. Accordingly,
we thought that the basicity of DMF might also led to the increase of the yield. Furthermore, other photocatalysts, 4CzIPN and 9-
mesityl-10-methylacridinium perchlorate, which can also act as strong oxidants at excited state, failed to deliver the desired product
(Table 1, entry 14-15). It was also noted that aqueous DMF (Table 1, entry 13) used in the reaction gave a superior product yield
compared with that of anhydrous DMF (Table 1, entry 16). With respect to the amount of catalyst and oxidant used in the reaction, 1.0
mol% of Eosin Y was found to be optimal, the model reaction was not completed with less or more than 1.0 mol% of Eosin Y (Table 1,
entries 13, 17-21), and no increased yield of 3a was observed with less or more than 3 equiv of K S O (Table 1, entries 13, 22-24).
2 2 8
Control experiments without oxidant, photocatalyst, oxygen or light resulted in lower yields of the target product, which showed that all
components were necessary for the optimized protocol (Table 1, entries 25−28). Therefore, optimal reaction conditions involved Eosin
2 2 8
Y (1.0 mol %) and K S O (3 eq.) in solvent free condition at room temperature under air atmosphere for 24 h.
Table 2. substrate scope of benzothiazolesa,b
N
R1
Eosin Y, K2S2O8, air
O
H
S
N
N
S
O
H
3
R1
+
N
+
15 W LED, r.t., 24 h
S
N
1
2a
R1
N
O
4
N
S
Cl
N
N
O
O
O
H
N
S
S
N
MeO
N
H
H
3
a, 68%
3
b, 58%
3c, 71%
N
Cl
N
S
N
O
N
N
N
S
O
MeO
S
O
4a, 12%
4b, trace
4c, 18%
N
S
N
N
S
O
O
O
N
S
N
2
O N
N
H
H
H
3
f, trace
3
d, 78%
3e, 79%
N
N
S
N
O
N
N
S
N
O2N
O
S
O
4d, 12%
4e, 10%
4f, trace
O
N
S
N
S
N
O
N
5a, 65%
5a', ND
aReaction conditions: benzothiazoles (1, 0.5 mmol), N,N-dimethylformamide
2a, 5 mL), K (3.0 equiv, 1.5 mmol), Eosin Y (1.0 mol%), open to the
(
2 2 8
S O
b
air, 15 W Blue LED (λ= 450 nm) at room temperature for 24 h. Isolated
yield.
With the conditions in hand, the scope of substituted benzothiazoles was investigated first in reactions with N,N-
dimethylformamide (Table 2). Generally, corresponding alkylated products (3) were smoothly produced in moderate to good yields
(58−79%) with acylated benzothiazoles (4) in low yields (10−18%). The results demonstrated that benzothiazole derivatives with 5-
chloro (3b), 6-methoxyl (3c), 4-methyl (3d) and 6-methyl (3e) substituents on the aromatic ring were well tolerated. Next, we
investigated the regioselectivity of the protocol. The reaction of benzothiazole with N-methylpyrrolidin-2-one (NMP) only gave 5a in
6
5% without 5a’, which indicated that the secondary amino carbon was preferred to construct the C-C bond.
To further investigate the substrate scope of this protocol, we evaluated various kinds of amides (2) in the reactions with
substituted benzothiazoles (Table 3). Much to our delight, N,N-dimethylacetamide (DMA) and N,N-dimethylpropanamide (DMP) also
tolerated the reaction conditions furnishing the desired products in moderate to excellent yields. The reactions of benzothiazole with
DMA and DMP gave 3g and 3s in 86% and 66% yields, respectively. Benzothiazoles with a 5-chloro (3i), 6-methoxyl (3j, 3t), 4-methyl
(3k, 3u), 6-methyl (3l, 3v) and 6-phenyl (3r) substituent on the aromatic ring gave corresponding alkylation products 3 in moderate to
good yields (45%-88%). However, the reactions of 6-cyano (3m) and 5-acetyl (3n) benzothiazoles with DMA only gave products in

4
Tetrahedron Letter
6
% and 7% yields, respectively. Benzothiazoles with 6-nitro (3h), 6-trifluoromethyl (3q) and 5-chloro (3w) only gave trace amount of
the alkylation product (3). Interestingly, benzothiazoles with 7-methoxyl (3o) and 4-phenyl (3p) did not react with DMA, whereas 6-
methoxyl (3j) and 6-phenyl (3r) benzothiazole gave product in 88% and 45%, respectively. The results showed that the reactions
seemed to be sensitive to the steric hindrance at 4- and 7-position of benzothiazoles. It is obvious that the isolated yields of the
corresponding products were decreased along with the increasement of chain length in the amides (3g, 3i, 3j, 3k, 3l compared to 3s,
1
3
w, 3t, 3u, 3v, respectively). The electronic characteristics of the substituents (R ) of benzothiazoles were found to have an effect on
the reactivity, where benzothiazoles with electron-withdrawing groups generally gave lower yields.
Table 3. substrate scope of N,N-dimethylamidesa,b
N
S
O
Eosin Y, K2S2O8, air
15 W LED, r.t., 24 h
N
S
R1
R1
O
+
N
R2
N
R2
1
2
3
N
S
Cl
O
N
S
N
N
S
O
O
O
O
2
O N
N
S
N
N
N
MeO
O
3
g, 86%
3h, trace
3i, 78%
3j, 88%
N
N
S
N
S
N
S
O
O
O
S
N
N
N
NC
N
3k, 85%
3m, 6%
3l, 81%
3n, 7%
Ph
N
N
S
N
S
N
O
O
O
O
S
N
N
F3C
N
Ph
S
N
OMe
3o, n.d.
3p, n.d.
3q, trace
3r, 45%
N
N
S
N
S
N
S
O
O
O
O
S
N
MeO
N
N
N
3s, 66%
3t,74%
3u, 72%
3v, 70%
Cl
N
S
O
N
3w, trace
aReaction conditions: benzothiazoles (1, 0.5 mmol), amides (2, 5 mL), K
S
2
O
2
8
(3.0 equiv,
1
.5 mmol), Eosin Y (1.0 mol%), open to the air, 15 W Blue LED (λ= 450 nm) at room
b
temperature for 24 h. Isolated yield.
N
S
O
N
O
H
O
N
TEMPO (2.0 eq)
Eosin Y, K2S2O8
N
H
N
N
S
N
S
O
H
O
N
+
N
3a
5a
air, r.t., 24 h
15 W Blue LED
1a
2a
S
N
O
O
1ab
N
N
O
4a
6a
N.D.
N.D.
Detected by LC-MS
Scheme 2. Control Experiment
For studying the possible mechanism of the transformation, a radical trapping agent TEMPO (2,2,6,6-tetramethyl-1-piperidiny-
loxy) was added under the optimal reaction conditions. Alkylated benzothiazole (3a), acylated benzothiazole (4a) and adduct of
benzothiazole (1ab) were not detected from the reaction mixture, and only adducts of DMF radicals with TEMPO (5a or 6a) were
observed by LC-MS (Scheme 2), which indicated that the transformation might occur through a radical pathway and benzothiazole
radical was not formed in the system.
According to the results of the control experiments, both Eosin YH
2 2 2 8
and K S O had certain catalytic effects when they acted alone,
and the catalytic effect was greatly improved when they worked together. Therefore, we speculated that the reaction may occur through
*
1
*
multiple routes (Scheme 3). Initially, the excited-state EYH
2 2 2
was generated from EYH by irradiation of visible light. EYH was
1
*
[24]
3
*
known to undergo fast ISC, which attributed to very brief (~0.5-2.7 ns) singlet EYH
98.8 μs) was typically considered to be the most relevant excited state in reactions.
2
life times, and thus, the triplet state EYH
A hydrogen atom transferred (HAT) between
2
[
24,25]
(
3
*
•
[26]
•
EYH
2
and DMF (2a) to produce EYH
3
and DMF radicals (2ab and 2ac). Photoredox cycle was closed by deprotonation of EYH
and sulfate anion radical SO
2 8
O . On the other hand, sulfate radical anion SO4 could react with the DMF (2a) through a hydrogen
3
[27]
•−
under the assistance of molecular oxygen O
peroxydisulfate dianion S
2
4
generated through homolytic cleavage of a
2
−
•−
−
[28]
abstraction process to form DMF radicals (2ab and 2ac) and HSO
4
.
The resulting DMF radicals (2ab and 2ac) would attack the 2-

[
29]
•[30]
position of benzothiazole (1a) to form radical cation intermediates (3ab or 4ab), which were deprotonated by the formed HO
2
or
•−
[26]
SO4 to give the products (3a and 4a). In addition, the structures of EYH
2
in neutral, excited-state and radical forms are listed below.
O
ISC
visible-light 1EYH *
3EYH2*
N
H
2
2a
Route I
O2
Route I
EYH2
HO2
EYH3
HSO4
O
HSO4
O
Route II
Route II
N
N
H
2ab
2ac
cleavage
S2O82-
SO4
N
O
H
S
1a
N
S
N
HSO4
H2O2
O
Route II
Route I
N
N
S
O
N
N
S
H
3a
H
H
N
S
O
N
3ab
4ab
HO2
4a
COOH
Br
COOH
Br
COOH
Br
Br
Br
Br
HO
visible light
+H
HO
O
O
HO
O
O
O
OH
Br
Br
Br
Br
Br
Br
EYH2
EYH2*
EYH3
Scheme 3. Plausible Mechanism
Conclusion
In conclusion, we have developed a two-component photocatalytic system for C2-alkylation reactions of benzothiazoles with N,N-
dimethylamides under solvent-free conditions mediated by visible light. Eosin Y, a cheap and readily available xanthene dye, was
applied as the photocatalyst and K S O , an inexpensive and readily available inorganic salt, acted as the oxidant. This reaction is mild
2 2 8
enough to tolerate various functional groups furnishing a series of coupling reactions in moderate to excellent yields. Current efforts in
our laboratory are directed toward applying two-component system to other alkylation reactions of heterocyclic compounds.
Acknowledgments
We are grateful for the financial support by the National Natural Science Foundation of China (No.30900959) and the Natural
Science Foundation of Zhejiang Province (LY17C140003).
References and notes
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2
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Graphical Abstract

Alkylation Reactions of Benzothiazoles with
N,N-dimethylamides catalyzed by the Two-Component
System under Visible Light
Leave this area blank for abstract info.
Jian-Quan Weng*, Wen-Xiu Xu, Xiao-Qiang Dai, Jun-Hui Zhang, Xing-Hai Liu
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
N
S
O
Eosin Y / K S O / air
N
S
2
2
8
R1
R1
+
N
O
R2
N
visible light, r.t., 24 h
R2
1
R = H, 5-Cl, 6-OMe, 4-Me, 6-Me,
up to 88% yield
6
-CN, 5-Ac, 6-Ph
2
R = H, Me, Et
visible light-mediated
solvent free
mild condition
Highlights



C2-amidoalkylation of benzothiazoles induced by visible light was developed.
Eosin Y/K S O acted as efficient two-component photocatalytic system.
This green protocol features mild conditions, broad substrates and high yields.
2
2
8