Sulfur-Promoted Redox Cyclization of 2,2′-Dinitrodiphenyl Disulfides and Benzylamines

Article abstract of DOI:10.1055/a-1430-5100

This study aims to develop green and sustainable advanced synthetic methods based on redox cyclization. Elemental sulfur is shown to promote the efficient synthesis of 2-substituted benzothiazoles from 2,2′-dinitrodiphenyl disulfides and benzylamines via redox cyclization in the absence of transition-metal catalysts and solvents. The 2-substituted benzothiazoles are obtained in good to excellent yields. This synthetic methodology is highly atom-economical and does not require any external oxidizing and/or reducing agents.

Full text of DOI:10.1055/a-1430-5100

SYNTHESIS
0
0
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9
-
7
8
8
1
1
4
3
7
-
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1
0
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–I
paper
A
en
M. Teramoto et al.
Paper
Synthesis
Sulfur-Promoted Redox Cyclization of 2,2′-Dinitrodiphenyl
Disulfides and Benzylamines
Masahiro Teramoto*a,b
R2
R2
R1
R1
Mitsutaka Imotoa
Motonori Takedaa
Takumi Mizuno*a
Akihiro Nomotob
Akiya Ogawab
NO2
S
N
S
S, Et3N
100 °C
+
NH2
0
0
0
0
-
0
0
0
2
-
4
2
0
0
-
9
4
4
7
2
redox cyclization
up to 94%
a Seika Corporation, 1660-627 Nishihama,
Wakayama 641-0036, Japan
m-teramoto@waseika.com
tmizuno@omtri.or.jp
b Department of Applied Chemistry, Graduate School of
Engineering, Osaka Prefecture University, 1-1 Gakuen-cho,
Naka-ku, Sakai, Osaka 599-8531, Japan
Corresponding Authors
Received: 20.02.2021
Accepted after revision: 12.03.2021
Published online: 12.03.2021
O
NH2
F
N
S
F
N
OMe
OMe
NH
·2HCl
NH2
S
DOI: 10.1055/a-1430-5100; Art ID: ss-2021-f0078-op
PMX 610
(anticancer agent)
Phortress (NSC 710305)
(anticancer agent)
Abstract This study aims to develop green and sustainable advanced
synthetic methods based on redox cyclization. Elemental sulfur is
shown to promote the efficient synthesis of 2-substituted benzothi-
azoles from 2,2′-dinitrodiphenyl disulfides and benzylamines via redox
cyclization in the absence of transition-metal catalysts and solvents.
The 2-substituted benzothiazoles are obtained in good to excellent
yields. This synthetic methodology is highly atom-economical and does
not require any external oxidizing and/or reducing agents.
+ Cl–
N
F
N
O
N
H
N
S
S
N
O
H
thioflavin
(fluorescent dye)
O
benthiavalicarb isopropyl
(fungicide)
Key words redox cyclization, benzothiazoles, 2,2′-dinitrodiphenyl di-
sulfides, benzylamines, elemental sulfur, atom-economical
N
S
N
N
S
S
n
To address the issues of increasing environmental pollu-
tion and the depletion of natural resources, significant ef-
forts have been devoted toward the development of greener
and more sustainable advanced chemical processes, partic-
ularly with regard to large-scale production. This study was
aimed to develop synthetic processes that meet at least one
of the following criteria: (1) high atom economy, (2) the in-
volvement of cascade reactions, and (3) transition-metal-
free and solvent-free reaction conditions.
The benzothiazole ring was a notable discovery in drug
research because of its diverse pharmacological activities.
This ring is present in numerous marine and terrestrial
plants that exhibit a wide range of pharmacological activi-
ties.1 Benzothiazoles are also valuable building blocks for
the construction of functional materials,2 agrochemicals,3
and polymers such as ABPBT and PBZT4 (Figure 1). Consid-
ering the practical utilities of benzothiazoles, it is impera-
tive to have effective methods for their synthesis.
n
poly(2,6-benzothiazole)
(ABPBT)
poly(p-phenylenebenzobisthiazole)
(PBZT)
Figure 1 Benzothiazoles as building blocks
tions of 2-halonitrobenzenes, benzylamines, and elemental
sulfur (Scheme 1, a).5
In these redox cyclization reactions, the starting materi-
als were subjected to two opposite reactions: reduction of
the corresponding nitrobenzenes and oxidation of benzyl-
amine. Such reactions are highly sought-after, as the three
processes, namely, oxidation, reduction, and condensation,
occur in a single step.
However, the synthesis of benzothiazoles from nitro-
benzenes is rather advanced at present. The iron-promoted
synthesis of 2-substituted benzothiazoles from nitroben-
zenes, elemental sulfur, and benzyl alcohol,6 or their syn-
thesis from nitrobenzenes, elemental sulfur, and methyl-
heteroarenes (or phenylacetic acids) in the absence of a
transition-metal catalyst have been reported.7,8
Nguyen et al. reported the synthesis of 2-arylbenzothi-
azoles, i.e., 2-substituted benzothiazoles, via the redox reac-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Teramoto et al.
Paper
Synthesis
The addition of a base (pyridine) increased the yield of
3aa to 90% (Table 1, entry 6). Decreasing or increasing the
sulfur concentration did not improve the yields of 3aa (en-
tries 7 and 8), while decreasing the concentration of 2a
lowered the yield of 3aa (entry 9). Increasing the concen-
tration of 2a did not improve the product yield (entry 10),
neither did altering the pyridine concentration (entries 11
and 12). Changing the reaction temperature and reaction
time also did not improve the yields (entries 13–16).
(a) From 2-halonitrobenzene, benzylamine, and elemental sulfur
NO2
N
S
pyridine
R1
R1
+
+
S
100 °C
X
X = F, Cl, Br, I
NH2
(b) From 2,2'-dinitrodiphenyl disulfide and phenylacetic acid
R1
R1
HO
NO2
S
FeCl2·4H2O, S
base, 130 °C
N
+
O
S
Finally, the effects of several other organic bases such as
triethylamine, N-methylmorpholine, and DBU were exam-
ined (Table 1, entries 17–19). The use of triethylamine gave
2
(c) This work:
Table 1 Optimization of the Reaction Conditionsa
R2
R2
R1
R1
NO2
N
S, Et3N
100 °C
NO2
+
N
S
S, base
solvent
S
S
NH2
S
+
S
2
NO2
NH2
Scheme 1 Synthesis of 2-substituted benzothiazoles via redox reac-
tions
1a
2a
3aa
Entry
2a
Sulfur
Solvent
Base
(mmol)
Temp
(°C)
Yield
(%)b
(mmol) (mmol)
Further, Nguyen et al. used 2,2′-dinitrodiphenyl disul-
fides and phenylacetic acids as starting materials for the el-
egant synthesis of 2-substituted benzothiazoles in the pres-
ence of a Fe/S catalyst (Scheme 1, b).9,10 However, the use of
phenylacetic acid is limited for general chemists. As pheny-
lacetic acid is used for the illicit production of phenylace-
tone, which, in turn, is used for manufacturing substituted
amphetamines, its availability is tightly controlled in coun-
tries such as the United States and China. In Japan, phenyl-
acetic acid is subject to the Stimulants Control Act as a raw
material for stimulants, and its import, manufacturing,
sales, and handling require permission from the Ministry of
Health, Labor and Welfare.
Considering this, we have developed the redox-cycliza-
tion-driven sulfur-promoted synthesis of 2-substituted
benzothiazoles from 2,2′-dinitrodiphenyl disulfides and
benzylamines in the absence of transition-metal catalysts
and solvents (Scheme 1, c). The mediating or catalyzing
ability of sulfur in this redox reaction lies in its ability to ex-
ist in multiple oxidation states, ranging from –2 to +6.
Initially, the synthesis of a 2-substituted benzothiazole
via sulfur-promoted redox cyclization was performed using
2,2′-dinitrodiphenyl disulfide (1a) and benzylamine (2a) as
model substrates. The reaction was conducted at 150 °C un-
der an argon atmosphere, and DMF, NMP, or sulfolane was
used as the solvent (Table 1, entries 1–3). Among these sol-
vents, the highest product yield was obtained in sulfolane
(entry 3). A good yield of the desired product, 2-phenylbenzo-
[d]thiazole (3aa), was obtained even at a lower reaction
temperature (100 °C) (entry 4). Interestingly, an excellent
yield (84%, 1.68 mmol) of 3aa was obtained for the solvent-
free reaction (entry 5).
1
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
4.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
none
DMF
none
none
none
none
none
2.5
150
150
150
100
100
100
100
100
100
100
100
100
80
60
68
78
66
84
90
69
64
60
89
85
77
62
65
68
81
94
80
61
81
6
2
NMP
3
sulfolane
sulfolane
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
4
5
6c
7c
2.5
8c
2.5
9c
2.5
10c
11c
12c
13c
14c
15c,d
16c,e
17f
18g
19h
20f,i
21f
2.5
1.3
5.0
2.5
2.5
120
100
100
100
100
100
100
100
2.5
2.5
2.5
2.5
2.5
2.5
2.5
a Reaction was conducted with 1a (1.0 mmol) in solvent (1.0 mL) for 24 h
under an argon atmosphere.
b GC yield.
c Pyridine was used.
d Reaction time was 8 h.
e Reaction time was 64 h.
f Triethylamine was used.
g N-Methylmorpholine was used.
h DBU was used.
i Under an air atmosphere.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

C
M. Teramoto et al.
Paper
Synthesis
3aa in an excellent yield (94%, 1.88 mmol) (entry 17). The
reactivity was lowered when the reaction was conducted in
air (entry 20), and the yield decreased significantly in the
absence of sulfur (entry 21).
The yield of 3aa in the presence of triethylamine (94%)
was remarkable because multiple processes, such as reduc-
tion of the nitro group, the redox reaction of benzylamine
with elemental sulfur, condensation, and cyclization, effi-
ciently proceeded in a single step to generate a heterocycle.
The safety and purity of the synthesized heterocycle are es-
sential for pharmaceuticals and electronic materials. Addi-
tionally, the use of transition-metal catalysts incurs signifi-
cant costs and involves substantial labor for removing the
residual metals. In view of these considerations, the
transition-metal-free reaction developed in this study has
significant advantage as a synthetic method.
With optimized conditions in hand, the substrate scope
and limitations of the sulfur-promoted redox cyclizations
of 2,2′-dinitrodiphenyl disulfides 1a–f with various benzyl-
amines 2a–l were investigated (Table 2).
Table 2 Substrate Scope of the Reaction between 2,2′-Dinitrodiphenyl Disulfides 1 and Benzylamines 2a
R2
R2
R1
R1
NO2
S
N
S
S, Et3N
100 °C
+
NH2
2
1a–f
2a–l
3aa–al
Entry
2a–l
3aa–al
Yield (%)b
1
2
3
4
5
6
3aa, R1 = H
81
44
81
75
56
70
3ba, R1 = CH3
3ca, R1 = OCH3
3da, R1 = CF3
3ea, R1 = Cl
3fa, R1 = Br
R1
N
S
2a
NH2
7
8
R1
3ab, R1 = H
78
56
N
S
H3C
H3C
2b
2c
3cb, R1 = OCH3
CH3
NH2
9
CH3
N
S
3ac
3ad
77
67
NH2
10
CH3
H3C
N
S
2d
NH2
11
12
13
N
S
tBu
tBu
2e
2f
3ae
3af
71
44
NH2
N
S
H3CO
OCH3
NH2
H3CO
OCH3
N
S
2g
2h
2i
3ag
3ah
3ai
76
74
71
NH2
NH2
14
15
N
S
Cl
Cl
Cl
Cl
N
S
NH2
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

D
M. Teramoto et al.
Paper
Synthesis
Table 2 (continued)
Entry
2a–l
3aa–al
Yield (%)b
64
Cl
Cl
N
S
16
2j
3aj
NH2
N
S
F3C
17
18
2k
2l
CF3
3ak
3al
66
74
NH2
N
S
F
F
NH2
a Reaction conditions: 1 (2.5 mmol), 2 (7.5 mmol), sulfur (5.0 mmol, 160 mg), triethylamine (6.25 mmol, 0.87 mL), 100 °C, 24 h, argon atmosphere.
b Yield of isolated product.
The sulfur-promoted synthesis of 3aa from 1a and 2a
was successfully performed and product 3aa was isolated in
a fairly good yield (81% isolated yield; 94% GC yield) (Table
2, entry 1). However, the reaction of 4,4′-dimethyl-2,2′-di-
nitrodiphenyl disulfide (1b) with 2a afforded 3ba in a much
lower yield of 44% (entry 2). Compound 1c bearing an elec-
tron-donating methoxy group and compound 1d bearing an
electron-deficient trifluoromethyl group gave 3ca and 3da
in fairly good yields of 81% and 75%, respectively (entries 3
and 4). The reactions of 4,4′-dichloro-2,2′-dinitrodiphenyl
disulfide (1e) and 4,4′-dibromo-2,2′-dinitrodiphenyl disul-
fide (1f) with 2a afforded 3ea and 3fa in good yields of 56%
and 70%, respectively (entries 5 and 6).
The reactions of 4-methylbenzylamine (2b) and 3-
methylbenzylamine (2c) with 1a gave 3ab and 3ac in good
yields of 78% and 77%, respectively (Table 2, entries 7 and
9). The reaction of 2-methylbenzylamine (2d) with 1a af-
forded 3ad in a good yield (67%) (entry 10). It is noteworthy
that the reaction proceeded despite the steric hindrance
from the ortho substituent. Additionally, the reaction of 2b
with 4,4′-dimethoxy-2,2′-dinitro-diphenyl disulfide (1c)
proceeded smoothly to afford 3cb in a reasonable 56% yield
(entry 8). Furthermore, the reaction of 1a and 4-tert-butyl-
benzylamine (2e) gave 3ae in a good yield of 71% (entry 11).
When an electron-donating methoxy group was present at
the 4-position, 3af was obtained in a low yield of 44% (entry
12). However, the reaction of 3-methoxybenzylamine (2g)
with 1a gave 3ag in a higher yield of 76% (entry 13).
tion of 1a and 2a afforded 3aa in a practical and useful iso-
lated yield of 85% (8.99 g, 42.6 mmol).
S (50 mmol, 1.60 g)
Et3N
(62.5 mmol, 8.6 mL)
NO2
N
S
S
+
S
100 °C, 24 h
NO2
NH2
1a
25 mmol, 7.71 g
2a
75 mmol, 8.2 mL
3aa
8.99 g, 42.6 mmol, 85%
Scheme 2 Gram-scale synthesis of 3aa
To determine the reaction intermediates, we examined
the reaction mixture by GC-MS, and discovered that N-ben-
zylidenebenzylamine (4a) and N-benzylbenzothioamide
(5a)11 were formed as byproducts during this reaction
(Scheme 3).
NH2
N
(a)
2
+
S
+
+
H2S
NH3
2a
4a
S
N
H
N
S
+
(b)
5a
4a
Scheme 3 Byproducts of the sulfur-promoted redox cyclization
Keeping this result in mind, several control experiments
were performed to investigate the reaction mechanism.
When the reaction was carried out using 2,2′-diaminodi-
phenyl disulfide (6a) instead of 2,2′-dinitrodiphenyl disul-
fide (1a), product 3aa was obtained in 8% GC yield (Scheme
4, a). This suggested that the nitro group was essential for
benzylamine oxidation.
Next, when the reaction was carried out using N-ben-
zylidenebenzylamine (4a) instead of benzylamine (2a), 3aa
was obtained in 77% GC yield (Scheme 4, b). This indicated
that 4a might be a reaction intermediate. In contrast, when
The reaction of 4-chlorobenzylamine (2h), 3-chloroben-
zylamine (2i), and 2-chlorobenzylamine (2j) with 1a afford-
ed products 3ah, 3ai, and 3aj in good yields of 74%, 71%, and
64%, respectively (Table 2, entries 14–16). The reactions of
benzylamines substituted with electron-deficient groups
[trifluoromethyl (2k) and fluoro (2l)] and 1a gave 3ak and
3al in good yields (entries 17 and 18).
Next, the feasibility of the gram-scale synthesis (ten-
fold) of 3aa was investigated (Scheme 2). Indeed, the reac-
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E
M. Teramoto et al.
Paper
Synthesis
NH2
N
S
S, Et3N
S
S
(a)
+
100 °C, 24 h
NH2
NH2
6a
2a
3aa, 8% (GC yield)
NO2
S
N
S
S, Et3N
N
(b)
+
S
100 °C, 24 h
NO2
3aa, 77% (GC yield)
4a
1a
S
NO2
N
S
S, Et3N
N
S
(c)
(d)
H
+
S
100 °C, 24 h
NO2
3aa, 12% (GC yield)
5a
1a
S, Et3N
TEMPO
NO2
N
S
S
+
S
100 °C, 24 h
NO2
NH2
1a
2a
3aa, 53% (GC yield)
Scheme 4 Control experiments for determining the reaction mechanism
the reaction was conducted using N-benzylbenzothioamide
(5a) instead of 2a, product 3aa was obtained in an unex-
pectedly low yield (12% GC yield) (Scheme 4, c), suggesting
that 5a was not a reaction intermediate. The addition of
three equivalents of TEMPO [(2,2,6,6-tetramethylpiperidin-
1-yl)oxyl] to the reaction system afforded 3aa resulted in a
53% GC yield (Scheme 4, d), suggesting that the mechanism
did not involve a radical reaction.
Based on the experimental results and information
available in the literature,6,12,13 a possible reaction pathway
is proposed (Scheme 5). Initially, 1a was subjected to a sev-
en-electron-reduction reaction to afford 2-aminothiophe-
nol (7a). Additionally, elemental sulfur was oxidized to sul-
furic acid via a three-electron-oxidation pathway. The reac-
tion of two equivalents of 2a and sulfur generated 4a as the
major product and ammonia and hydrogen sulfide as by-
NO2
NH2
1
1
1
+
H2SO4
S
+
+
[4H]
/
2
S
/
2
/
2
S
SH
NO2
1a
7a
NH2
N
2
S
+
+
NH3
+
H2S
2a
4a
N
NH2
+
7a
8a
+
4a
SH
8a
2a
N
S
+
[2 H]
+
[2H]
H2S
S
3aa
NO2
N
S
NH2
1
1
+
1
S
+
+
S
(NH4)2SO4
/
2
/
/
2
2
S
NO2
3aa
1a
2a
Scheme 5 A plausible reaction pathway for the formation of 3aa
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

F
M. Teramoto et al.
Paper
Synthesis
products. The condensation of 7a and 4a afforded 8a and
2a. Compound 8a then underwent oxidative cyclization to
form 3aa via a two-electron-oxidation pathway. Finally, hy-
drogen sulfide was reconverted into elemental sulfur via a
two-electron-oxidation pathway. Based on these observa-
tions, it was concluded that 1a reacted with sulfur and 2a to
produce 3aa and ammonium sulfate (Scheme 5).
2-Phenylbenzo[d]thiazole (3aa)
Recrystallized from ethanol; Rf = 0.31 (hexane/ethyl acetate = 50:1);
yellowish-white needle crystal; yield: 854 mg (81%); mp 113–114 °C
(Lit.6 108–111 °C).
FTIR (KBr): 3064, 1478, 1454, 1433, 1313, 1225, 963, 767, 687, 623
cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.11–8.08 (m, 3 H), 7.92 (d, J = 7.6 Hz, 1
H), 7.51–7.49 (m, 4 H), 7.40 (t, J = 7.6 Hz, 1 H).
In summary, we have developed the sulfur-promoted
synthesis of 2-substituted benzothiazoles 3 using 2,2′-dini-
trodiphenyl disulfides 1 and benzylamines 2. The reaction
proceeds via a redox pathway and does not require a transi-
tion-metal catalyst. Moreover, the products are obtained in
excellent yields. The multiple reaction steps, including re-
duction of the nitro group, the redox reaction of benzyl-
amine with elemental sulfur, condensation, and cyclization,
occur in a single step to afford 2-substituted benzothiazoles
3. Steps such as product isolation and purification can be
largely eliminated from this reaction in contrast to the cases
when the reactions are conducted sequentially. This meth-
od is superior from the viewpoint of process chemistry and
atom-economy. Further investigations of the mechanism
and applications of this reaction are currently underway.
13C{1H} NMR (151 MHz, CDCl3):  = 168.2, 154.3, 135.2, 133.7, 131.1,
129.2, 127.7, 126.5, 125.3, 123.4, 121.8.
5-Methyl-2-phenylbenzo[d]thiazole (3ba)
Recrystallized from ethanol; Rf = 0.17 (hexane/ethyl acetate = 50:1);
reddish-brown needle crystal; yield: 396 mg (44%); mp 141–143 °C
(Lit.6 145–146 °C).
1H NMR (600 MHz, CDCl3):  = 8.09 (dd, J = 2.1, 7.3 Hz, 2 H), 7.89 (s, 1
H), 7.77 (d, J = 8.3 Hz, 1 H), 7.50–7.48 (m, 3 H), 7.22 (d, J = 8.3 Hz, 1 H),
2.52 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3):  = 168.3, 154.7, 136.5, 133.9, 132.1,
131.0, 129.1, 127.6, 126.9, 123.4, 121.2, 21.7.
5-Methoxy-2-phenylbenzo[d]thiazole (3ca)
Recrystallized from ethanol; Rf = 0.12 (hexane/ethyl acetate = 50:1);
pale orange needle crystal; yield: 981 mg (81%); mp 71–72 °C (Lit.15
75–77 °C).
1H NMR (600 MHz, CDCl3):  = 8.08 (dd, J = 2.1, 7.8 Hz, 2 H), 7.75 (d, J =
8.9 Hz, 1 H), 7.58 (d, J = 2.8 Hz, 1 H), 7.49–7.48 (m, 3 H), 7.04 (dd, J =
2.8, 8.9 Hz, 1 H), 3.91 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3):  = 169.4, 159.3, 155.5, 133.9, 131.0,
129.2, 127.5, 127.0, 122.0, 115.7, 105.6, 55.8.
Chemicals were purchased from commercial sources and used with-
out further purification. 2,2′-Dinitrodiphenyl disulfides 1c, 1d, and 1f
were prepared according to literature methods.14 Analytical thin-lay-
er chromatography was carried out on silica gel plates, and com-
pounds were visualized using shortwave (254 nm) UV light. Column
chromatography was accomplished using silica gel. Melting points
were determined with a YAMATO MP-21 instrument (Yamato Scien-
tific Co., Ltd., Tokyo, Japan) and are uncorrected. FTIR spectra were re-
corded on a JASCO FT/IR-4100 instrument (JASCO Corporation, Tokyo,
Japan) as a function of the wavenumbers (cm–1). 1H, 13C, and 19F NMR
spectra were obtained on a JEOL JNM-ECA600 instrument (JEOL Ltd.,
Tokyo, Japan). 1H NMR spectra were recorded at 600 MHz using CDCl3
as the solvent and are referenced to CHCl3 (7.26 ppm). 13C NMR spec-
tra were recorded at 151 MHz in CDCl3 using CDCl3 (77.16 ppm) as
the standard. 19F NMR spectra were recorded at 565 MHz in CDCl3 us-
ing trifluoroacetic acid (–78.5 ppm) as an external standard. Chemical
shifts are reported in parts per million (ppm), and coupling constants
are reported in hertz (J, Hz). GC-MS analyses were performed on a
GC6890N-JMS-K9 instrument (Agilent, Santa Clara, USA).
2-Phenyl-5-trifluoromethylbenzo[d]thiazole (3da)
Recrystallized from ethanol; Rf = 0.29 (hexane/ethyl acetate = 50:1);
yellow needle crystal; yield: 1.05 g (75%); mp 128–130 °C (Lit.16
132.3 °C).
1H NMR (600 MHz, CDCl3):  = 8.34 (s, 1 H), 8.12–8.10 (m, 2 H), 8.02
(d, J = 8.3 Hz, 1 H), 7.63 (d, J = 8.3 Hz, 1 H), 7.54–7.51 (m, 3 H).
13C{1H} NMR (151 MHz, CDCl3):  = 170.3, 153.9, 138.6, 133.2, 131.7,
129.3, 129.2 (q, J = 31.8 Hz), 127.9, 126.2 (q, J = 271.2 Hz), 122.4, 121.7
(q, J = 4.3 Hz), 120.5 (q, J = 4.3 Hz).
19F{1H} NMR (565 MHz, CDCl3)  = –62.6.
5-Chloro-2-phenylbenzo[d]thiazole (3ea)
Recrystallized from ethanol; Rf = 0.30 (hexane/ethyl acetate = 50:1);
light brown plate-like crystal; yield: 689 mg (56%); mp 137–139 °C
(Lit.17 138–139 °C).
1H NMR (600 MHz, CDCl3):  = 8.09–8.07 (m, 2 H), 8.06 (d, J = 2.1 Hz, 1
H), 7.81 (d, J = 8.9 Hz, 1 H), 7.53–7.49 (m, 3 H), 7.37 (dd, J = 2.1, 8.3 Hz,
1 H).
2-Substituted Benzothiazoles 3; General Procedure
To a 15 mL oven-dried reaction vessel were added 2,2′-dinitrodiphe-
nyl disulfide 1 (2.5 mmol), benzylamine 2 (7.5 mmol), sulfur (5.0
mmol, 160 mg), and triethylamine (6.25 mmol, 0.87 mL) under an ar-
gon atmosphere. The reaction vessel was sealed and the contents
stirred at 100 °C for 24 h. After completion of the reaction, the mix-
ture was extracted with ethyl acetate and water. The organic layer
was dried over anhydrous MgSO4 and the solvent was removed under
reduced pressure. The crude residue was purified by recrystallization
and column chromatography on silica gel (hexane/ethyl acetate) to af-
ford the desired product 3.
13C{1H} NMR (151 MHz, CDCl3):  = 170.1, 155.1, 133.5, 133.4, 132.5,
131.5, 129.2, 127.8, 125.8, 123.2, 122.5.
5-Bromo-2-phenylbenzo[d]thiazole (3fa)
Recrystallized from ethanol; Rf = 0.30 (hexane/ethyl acetate = 50:1);
yellowish-white needle crystal; yield: 809 mg (70%); mp 132–133 °C
(Lit.18 135–136 °C).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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M. Teramoto et al.
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1H NMR (600 MHz, CDCl3):  = 8.22 (d, J = 2.1 Hz, 1 H), 8.07 (dd, J = 2.1,
7.2 Hz, 2 H), 7.75 (d, J = 8.9 Hz, 1 H), 7.52–7.48 (m, 4 H).
13C{1H} NMR (151 MHz, CDCl3):  = 169.8, 155.4, 134.0, 133.3, 131.5,
2-(4′-Methoxyphenyl)benzo[d]thiazole (3af)
Recrystallized from ethanol; Rf = 0.23 (hexane/ethyl acetate = 40:1);
yellowish-white needle crystal; yield: 527 mg (44%); mp 119–120 °C
(Lit.19 115–116 °C).
129.2, 128.4, 127.8, 126.2, 122.8, 120.0.
1H NMR (600 MHz, CDCl3):  = 8.05–8.03 (m, 3 H), 7.87 (d, J = 7.6 Hz, 1
H), 7.47 (t, J = 8.3 Hz, 1 H), 7.35 (t, J = 8.3 Hz, 1 H), 7.00 (dt, J = 2.4, 8.9
Hz, 2 H), 3.88 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3):  = 168.0, 162.0, 154.4, 135.0, 129.2,
126.6, 126.3, 124.9, 122.9, 121.6, 114.5, 55.6.
2-(4′-Tolyl)benzo[d]thiazole (3ab)
Recrystallized from ethanol; Rf = 0.21 (hexane/ethyl acetate = 40:1);
light yellow needle crystal; yield: 877 mg (78%); mp 80–82 °C (Lit.19
80–82 °C).
1H NMR (600 MHz, CDCl3):  = 8.07 (d, J = 8.3 Hz, 1 H), 7.99 (d, J = 7.6
Hz, 2 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 1 H), 7.37 (t, J = 7.6
Hz, 1 H), 7.30 (d, J = 8.3 Hz, 2 H), 2.42 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3):  = 168.3, 154.3, 141.5, 135.0, 131.1,
129.8, 127.6, 126.3, 125.1, 123.1, 121.7, 21.6.
2-(3′-Methoxyphenyl)benzo[d]thiazole (3ag)
Recrystallized from ethanol; Rf = 0.30 (hexane/ethyl acetate = 50:1);
white plate-like crystal; yield: 919 mg (76%); mp 83–84 °C (Lit.22 81–
82 °C).
1H NMR (600 MHz, CDCl3):  = 8.08 (d, J = 8.3 Hz, 1 H), 7.91 (d, J = 8.3
Hz, 1 H), 7.68 (s, 1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.50 (t, J = 8.3 Hz, 1 H),
7.42–7.38 (m, 2 H), 7.05 (dd, J = 2.1, 8.3 Hz, 1 H), 3.92 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3):  = 168.1, 160.2, 154.2, 135.2, 135.0,
130.2, 126.5, 125.4, 123.4, 121.8, 120.4, 117.5, 112.2, 55.7.
5-Methoxy-2-(4′-tolyl)benzo[d]thiazole (3cb)
Recrystallized from ethanol; Rf = 0.06 (hexane/ethyl acetate = 50:1);
yellow-orange needle crystal; yield: 719 mg (56%); mp 101–102 °C
(Lit.20 99–100 °C).
1H NMR (600 MHz, CDCl3):  = 7.96 (d, J = 7.6 Hz, 2 H), 7.73 (d, J = 8.9
Hz, 1 H), 7.56 (s, 1 H), 7.29 (d, J = 8.3 Hz, 2 H), 7.02 (dd, J = 1.4, 8.3 Hz,
1 H), 3.91 (s, 3 H), 2.43 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3):  = 169.6, 159.2, 155.5, 141.5, 131.2,
129.8, 127.4, 126.9, 121.9, 115.4, 105.5, 55.8, 21.7.
2-(4′-Chlorophenyl)benzo[d]thiazole (3ah)
Recrystallized from ethanol; Rf = 0.35 (hexane/ethyl acetate = 50:1);
yellowish-orange block crystal; yield: 907 mg (74%); mp 115–116 °C
(Lit.18 118–120 °C).
1H NMR (600 MHz, CDCl3):  = 8.07 (d, J = 8.3 Hz, 1 H), 8.02 (d, J = 8.9
Hz, 2 H), 7.89 (d, J = 8.3 Hz, 1 H), 7.50 (t, J = 8.3 Hz, 1 H), 7.46 (d, J = 8.9
Hz, 2 H), 7.39 (t, J = 8.3 Hz, 1 H).
13C{1H} NMR (151 MHz, CDCl3):  = 166.7, 154.2, 137.1, 135.2, 132.2,
129.4, 128.8, 126.6, 125.5, 123.4, 121.8.
2-(3′-Tolyl)benzo[d]thiazole (3ac)
Recrystallized from ethanol; Rf = 0.25 (hexane/ethyl acetate = 50:1);
yellowish-white crystal; yield: 869 mg (77%); mp 69–70 °C (Lit.19 63–
66 °C).
1H NMR (600 MHz, CDCl3):  = 8.09 (d, J = 8.3 Hz, 1 H), 7.95 (s, 1 H),
7.91 (d, J = 8.3 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 7.51–7.48 (m, 1 H),
7.38 (t, J = 8.3 Hz, 2 H), 7.30 (d, J = 7.5 Hz, 1 H), 2.46 (s, 3 H).
2-(3′-Chlorophenyl)benzo[d]thiazole (3ai)
Recrystallized from ethanol; Rf = 0.17 (hexane/ethyl acetate = 50:1);
yellow prism; yield: 877 mg (71%); mp 95–97 °C (Lit.23 96 °C).
13C{1H} NMR (151 MHz, CDCl3):  = 168.5, 154.2, 139.0, 135.2, 133.6,
1H NMR (600 MHz, CDCl3):  = 8.13–8.12 (m, 1 H), 8.09 (d, J = 8.3 Hz, 1
H), 7.95 (d, J = 7.6 Hz, 1 H), 7.92 (d, J = 8.3 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1
H), 7.48–7.41 (m, 3 H).
131.9, 129.1, 128.1, 126.4, 125.3, 125.0, 123.3, 121.7, 21.5.
2-(2′-Tolyl)benzo[d]thiazole (3ad)
13C{1H} NMR (151 MHz, CDCl3):  = 166.4, 154.1, 135.4, 135.3, 135.2,
131.0, 130.4, 127.6, 126.7, 125.8, 125.7, 123.6, 121.8.
Recrystallized from ethanol; Rf = 0.33 (hexane/ethyl acetate = 50:1);
red-orange plate-like crystal; yield: 756 mg (67%); mp 53–54 °C (Lit.19
51–53 °C).
1H NMR (600 MHz, CDCl3):  = 8.12 (d, J = 8.3 Hz, 1 H), 7.94 (d, J = 8.5
Hz, 1 H), 7.77 (d, J = 7.1 Hz, 1 H), 7.52 (td, J = 1.3, 7.1 Hz, 1 H), 7.43–
7.31 (m, 4 H), 2.67 (s, 3 H).
2-(2′-Chlorophenyl)benzo[d]thiazole (3aj)
Recrystallized from ethanol; Rf = 0.30 (hexane/ethyl acetate = 50:1);
yellowish-white needle crystal; yield: 790 mg (64%); mp 78–79 °C
(Lit.24 80–82 °C).
13C{1H} NMR (151 MHz, CDCl3):  = 168.1, 153.9, 137.4, 135.7, 133.2,
1H NMR (600 MHz, CDCl3):  = 8.23–8.21 (m, 1 H), 8.15 (d, J = 8.3 Hz, 1
H), 7.96 (d, J = 8.3 Hz, 1 H), 7.55–7.52 (m, 2 H), 7.45–7.40 (m, 3 H).
131.7, 130.7, 130.1, 126.3, 126.2, 125.2, 123.5, 121.5, 21.5.
2-(4′-tert-Butylphenyl)benzo[d]thiazole (3ae)
13C{1H} NMR (151 MHz, CDCl3):  = 164.3, 152.6, 136.2, 132.8, 132.4,
Recrystallized from ethanol; Rf = 0.30 (hexane/ethyl acetate = 50:1);
yellowish needle crystal; yield: 945 mg (71%); mp 104–105 °C (Lit.21
104–105 °C).
1H NMR (600 MHz, CDCl3):  = 8.07 (d, J = 7.6 Hz, 1 H), 8.03 (d, J = 8.3
Hz, 2 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 2 H), 7.49 (t, J = 7.6
Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 1.37 (s, 9 H).
131.9, 131.3, 130.9, 127.2, 126.4, 125.6, 123.6, 121.5.
2-(4′-Trifluoromethylphenyl)benzo[d]thiazole (3ak)
Recrystallized from ethanol; Rf = 0.21 (hexane/ethyl acetate = 50:1);
white needle crystal; yield: 916 mg (66%); mp 157–159 °C (Lit.16
157.4 °C).
1H NMR (600 MHz, CDCl3):  = 8.20 (d, J = 8.3 Hz, 2 H), 8.11 (d, J = 8.3
Hz, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 2 H), 7.53 (t, J = 7.6
Hz, 1 H), 7.43 (t, J = 7.6 Hz, 1 H).
13C{1H} NMR (151 MHz, CDCl3):  = 168.3, 154.7, 154.4, 135.1, 131.0,
127.5, 126.4, 126.1, 125.1, 123.2, 121.7, 35.1, 31.3.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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M. Teramoto et al.
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13C{1H} NMR (151 MHz, CDCl3):  = 166.2, 154.2, 136.9, 135.4, 132.6
(q, J = 33.2 Hz), 127.9, 126.8, 126.2 (q, J = 4.3 Hz), 125.9, 124.0 (q, J =
272.6 Hz), 123.8, 121.9.
Reaction of 2,2′-Dinitrodiphenyl Disulfide (1a) with Benzylamine
(2a) in the Presence of TEMPO (Scheme 4, d)
To a 15 mL oven-dried reaction vessel were added 2,2′-dinitrodiphe-
nyl disulfide (1a) (1.0 mmol, 308 mg), benzylamine (2a) (3.0 mmol,
0.33 mL), sulfur (2.0 mmol, 64 mg), triethylamine (2.5 mmol, 0.34
mL), and TEMPO (3.0 mmol, 469 mg) under an argon atmosphere. The
reaction vessel was sealed and the contents stirred at 100 °C for 24 h.
The product 3aa was obtained in 53% GC yield (1.06 mmol).
19F{1H} NMR (565 MHz, CDCl3)  = –62.5.
2-(4′-Fluorophenyl)benzo[d]thiazole (3al)
Recrystallized from ethanol; Rf = 0.17 (hexane/ethyl acetate = 50:1);
yellowish-white needle crystal; yield: 843 mg (74%); mp 99–100 °C
(Lit.13 99–101 °C).
1H NMR (600 MHz, CDCl3):  = 8.11–8.08 (m, 2 H), 8.06 (d, J = 8.3 Hz, 1
H), 7.90 (d, J = 8.3 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1
H), 7.19 (t, J = 8.3 Hz, 2 H).
Conflict of Interest
The authors declare no conflict of interest.
13C{1H} NMR (151 MHz, CDCl3):  = 166.9, 164.6 (d, J = 251.4 Hz),
154.2, 135.2, 130.1 (d, J = 2.9 Hz), 129.7 (d, J = 8.7 Hz), 126.6, 125.4,
123.3, 121.8, 116.3 (d, J = 21.7 Hz).
Acknowledgment
19F{1H} NMR (565 MHz, CDCl3)  = –107.5.
The authors wish to thank Dr. Takeo Nakai and Dr. Masatoshi Mihara
(Osaka Research Institute of Industrial Science and Technology) for
useful discussions.
Gram-Scale Synthesis of 3aa
2-Phenylbenzo[d]thiazole (3aa) was prepared from a mixture of 2,2′-
dinitrodiphenyl disulfide (1a) (7.71 g, 25 mmol), benzylamine (2a)
(8.2 mL, 75 mmol), sulfur (1.60 g, 50 mmol), and triethylamine (8.6
mL, 62.5 mmol) under an argon atmosphere according to the general
procedure [100 °C (oil bath), 24 h]. After the reaction reached comple-
tion, the mixture was diluted with ethyl acetate. The organic layer
was washed with water and brine and dried over anhydrous MgSO4.
The solvent was removed under reduced pressure and the crude resi-
due was purified by recrystallization and column chromatography on
silica gel (hexane/ethyl acetate = 50:1) to afford pure product 3aa
(8.99 g, 85%).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1430-5100.
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In a 15 mL oven-dried reaction vessel, 2,2′-dinitrodiphenyl disulfide
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I