A metal-free and recyclable synthesis of benzothiazoles using thiourea as a sulfur surrogate

Article abstract of DOI:10.1016/j.tetlet.2015.02.054

Using odorless thiourea as the S source, benzothiazoles and asymmetric disulfides could be obtained from thioformanilides through the tandem cyclization/nucleophilic addition/hydrolysis/nucleophilic substitution reaction. Furthermore, the obtained asymmetric disulfides could readily transfer to benzothiazoles after nitro-reduction and amide formation reaction. This metal-free and recyclable synthetic methodology offered a time-efficient, less expensive, and environmentally friendly alternative to multifunctional benzothiazoles.

Full text of DOI:10.1016/j.tetlet.2015.02.054

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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A metal-free and recyclable synthesis of benzothiazoles using
thiourea as a sulfur surrogate
a
a
a
a
a
a
Yan Yin a,b, , Hong Zhou , Xichen Liu , Haiying Chen , Fanhong Wu , Heng Zhang , Ruiheng Tao ,
⇑
Fengkai Cheng a, Yangbo Feng c
a School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Rd., Shanghai 200032, China
c Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Florida, Jupiter, FL 33458, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Using odorless thiourea as the S source, benzothiazoles and asymmetric disulfides could be obtained from
thioformanilides through the tandem cyclization/nucleophilic addition/hydrolysis/nucleophilic substitu-
tion reaction. Furthermore, the obtained asymmetric disulfides could readily transfer to benzothiazoles
after nitro-reduction and amide formation reaction. This metal-free and recyclable synthetic method-
ology offered a time-efficient, less expensive, and environmentally friendly alternative to multifunctional
benzothiazoles.
Received 7 January 2015
Revised 5 February 2015
Accepted 13 February 2015
Available online xxxx
Keywords:
Benzothiazoles
Thiourea
Ó 2015 Elsevier Ltd. All rights reserved.
Isothiouronium salt
TFA
ROCK inhibitors
Introduction
SH
S
N
Y
a
b
R
+
R
Z
The benzothiazole moiety is an important architecture due to
its widespread occurrence in bioactive natural products, pharma-
ceuticals, organic optoelectronic materials, and ligands for phos-
phorescent complexes.1 The most common method to prepare
this building block involves condensations of an ortho-amino thio-
phenol with an aromatic aldehyde, carboxylic acid, acyl chloride, or
nitrile under a wide set of reaction conditions (Fig. 1a).2 However,
this methodology suffered from the disadvantages in preparation
of ortho-amino thiophenol derivatives, and the odors from thiophe-
nols lead to bad environmental problems in work-up processes. An
alternative strategy for the synthesis of benzothiazoles is ring clo-
sure of thioformanilides, which needs sulfur reagents such as P4S10
or Lawesson’s reagent to convert the amides to corresponding
thioamides (Fig. 1b).3 Itoh and Mase published a novel synthesis
of benzothiazoles via Pd-catalyzed cross-coupling of 2-haloanilides
with thiols followed by base- or TFA-promoted cyclization.4 In this
transformation the R1 group linked to the S atom acted as the pro-
tected group to introduce sulfur to the molecule and was discarded
as waste without recovery after the cyclization reaction (Fig. 1c).
Recently, several copper-catalyzed approaches to benzothiazoles
NH2
Lawesson's reagent
or P4S10
X
X
O
S
S
N
R
N
H
R
N
H
R
X = H, Cl, Br, I, SMe,OCH3
NaOEt
or TFA
thiols
X
S
N
O
cat. Pd
R
O
c
R
NH
S
R1
N
H
R
R
Inorganic sulfur
cat.CuI
X
S
O
R
d
N
H
N
Figure 1. Synthesis of benzothiazoles.
were reported in good yields using inorganic sulfur as sulfur
sources (Fig. 1d).5 Although much attention has been paid to the
construction of the benzothiazole unit, development of new syn-
thetic methodologies for this privileged structure is still an impor-
tant and challenging task for the chemistry community.
We have previously discovered a series of benzothiazole deriva-
tives as ROCK inhibitors with good biochemical and cellular
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2015.02.054
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yin, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.02.054

2
Y. Yin et al. / Tetrahedron Letters xxx (2015) xxx–xxx
1. Previous synthesis
O2N
Table 1
Survey of the cyclization conditionsa
OCH3
NO2
R1
NH2
F
R1
S
O
S
R1
C H O
OCH
3
2
5
OCH3
O
N
S
NH
Additive
Br
Br
Br
O
S
A
B
C
OC H
2
5
R1
NHCOR2
R1
OCH3
MW
N
S
1a
2
S
R2
Br
Br
D
E
Entry Additive
Solvent
Temp
(°C)
Time
(h)
Yield
(%)
2. Present work
NHR2
S
NO2
TFA, SC(NH2)2,
1
2c
3c
4c
5c
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
—
80
80
80
80
80
2
2
2
2
2
95b
S
then 1M NaOH, 1-Fluoro-2-nitro-benzene
S
N
CH2Cl2
CHCl3
Toluene
Trace
Trace
Trace
Trace
+
R2
D
B
E
1, SnCl2.2H2O, rt
2, R2COCl, Py. DCM
OCH3
H3CO
Trifluoromethyl-
benzene
6c
7c
CF3COOH
HCOOH
HCOOH
CH3COOH
CH3COOH
—
—
—
—
—
rt
2
2
18
2
Trace
Trace
95b
N/R
Trace
Figure 2. Synthetic route of benzothiazoles.
110
110
110
110
8
9c
potencies and sufficient kinase selectivity.6 The benzothiazole core
was accessed in 4 steps including thionation, nitro reduction,
amide coupling, and microwave-assisted cyclization. In this report-
ed synthetic route, odorous 4-methoxyl-benzyl mercaptan was
used as the sulfur source to introduce sulfur atom through thiona-
tion reaction of 2-fluoro-1-nitro-benzene derivatives (A), and the
benzyl group linked to S atom acted as a leaving group and did
not recover after the cyclization reaction (Fig. 2, 1).6 A new syn-
thetic route was recently developed in our lab. In this new route,
only 3 steps were needed to build up the benzothiazole moiety
(E, Fig. 2), and odorless thiourea was used as the S source. This
new route is more time-efficient, less expensive, and more envi-
ronmental friendly (Fig. 2, 2). Herein, the development of a met-
al-free and recyclable synthesis of benzothiazoles with thiourea
as the sulfur source is discussed in detail, and a novel synthesis
of the key intermediate of SR6494, an important benzothiazole-
based ROCK inhibitor, is also reported.
10c
24
a
b
c
Conditions: 1a (0.2 mmol), additive (0.1 mL), solvent (0.2 mL).
Isolated yield based on 1a.
Unconsumed 1a was recovered.
Substrates 1b–1e, which contain the 2-OCH3, 2,4,6-OCH3, 4-H, or
4-Cl substitution on the phenyl ring, were prepared and subjected
to the cyclization and the results are shown in Table 2. All sub-
strates containing the methoxy group underwent the reaction
smoothly and gave product 2 in high yields within 2 h no matter
what was the substitution position on the phenyl ring (Table 2,
entries 1–3). However, no cyclizations were observed when 1d
(with no substitution) and 1e (with the electronic withdrawing
group (Cl) at para position) were treated with TFA (Table 2, entries
4 and 5). Increasing the reaction time to 24 h led to anilines
because the amide bond was unstable under acid conditions for a
long time. These results suggested that the presence of methoxy
groups could stabilize the benzyl cation intermediates derived
from 1a to 1c as compared to that 1d and 1e.
Results and discussion
We initially screened the reaction conditions including additive,
solvent, temperature, and reaction time to optimize the synthesis
of benzothiazoles with N-[2-(4-methoxy-benzylsulfanyl)-phenyl]-
oxalamic acid ethyl ester 1a as the substrate of the model reaction
(Table 1). With excess TFA (CF3COOH), thioformanilide 1a was
transferred to benzothiazole-2-carboxylic acid ethyl ester 2 in
95% yield after 2 h at 80 °C (Table 1, entry 1). The addition of sol-
Methoxylbenzyl cations could be seized by nucleophiles such as
thiourea.7 Thiourea was thus added to the mixture of 1 in TFA to
study the tandem cyclization/nucleophilic addition. The results
were just what we expected and are shown in Table 3. Cooking
1a with TFA and thiourea for 2 h, both benzothiazole 2 and
benzylisothiouronium TFA salt 3a were obtained in 95% equal
yields (Table 3, entry 1). 1b and 1c also underwent the tandem
vent such as CH2Cl2, CHCl3, toluene, and
a,a,a-trifluorotoluene to
the reaction mixture slowed down the reaction and only trace
amount of products was obtained after 2 h as detected by TLC ana-
lysis (Table 1, entries 2–5). If running the TFA-promoted reaction at
room temperature without any solvents, the conversion of 1a to 2
was very slow and only a small amount of 2 was observed by TLC
analysis after 2 h and the conversion could not completely finish
even by prolonging the reaction rime to 24 h (Table 1, entry 6).
Changing the additive from TFA to formic acid (HCOOH) or acetic
acid (CH3COOH), trace or no products were obtained after heating
the mixture for 2 h at 110 °C, respectively (Table 1, entries 7 and 9).
By prolonging the reaction time to 18 h, a yield of 95% was
obtained with formic acid as the additive (Table 1, entry 8). How-
ever, still only trace amount of products was observed using acetic
acid (Table 1, entry 9). Therefore, TFA was very important for this
intramolecular cyclization and will be used as the additive in fur-
ther investigation.
Table 2
Survey of the cyclization conditionsa
O
O
N
S
C H O
2
5
NH
+ TFA
O
S
OC H
2
5
R
1
R
= 4-OCH 1a, 2-OCH 1b,
3 3
1
2
2,4,6-OCH 1c, 4-H 1d, 4-Cl 1e
3
Entry
Substrate
Time (h)
Yield of 2b (%)
1
2
3
4
5
1a
1b
1c
1d
1e
2
2
2
2
2
95
90
95
N/Rc
N/Rc
The 4-methoxy-benyl group in 1a was proved to be a good pro-
tecting group for this TFA-promoted cyclization. In addition, we
also investigated a few other protecting groups for this conversion.
a
b
c
Conditions: 1 (0.2 mmol), TFA (0.1 mL), 80 °C.
Isolated yield based on 1.
1 was recovered.
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Y. Yin et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 3
Table 4
Tandem cyclization/nucleophilic additiona
Tandem cyclization/nucleophilic addition/hydrolysis/nucleophilic substitution
reactiona
COOEt
S
NHCOCOOEt
NH2
COOEt
NHCOCOOEt
N
CF3COO
S
+
TFA, SC(NH2)2
+ TFA + SC(NH2)2
S
N
S
NH2
+
O
O
S
+
R1
R1
then base, R-X
S
S R
OCH3
2
R1 = 4-OCH3 1a, 2-OCH3 1b,
2,4,6-OCH3 1c, 4-H 1d, 4-Cl 1e
1a
2
4
6
2
3
Entry R–X
Structure of 6b
Yield of Yield of
Entry
Substrate
Time (h)
Yield of 2b (%)
Yield of 3b (%)
6b
4b
1
2
1a
1b
1c
1d
1e
2
2
2
2
2
95
95
95
N/R
N/R
95
95
95
N/R
N/R
S
1
2
n-BuBr
60
11
O
3
6a
4c
5c
S
1-Bromo-
heptane
O
61
63
10
9
a
b
c
Conditions: 1 (0.2 mmol), TFA (0.1 mL), thiourea (0.2 mmol), 80 °C.
Isolated yield based on 1.
1 was recovered.
6b
Br
O
S
3
4
6c
cyclization/nucleophilic addition smoothly, and good yields were
obtained after 2 h (Table 3, entries 2 and 3). On the other hand,
no reactions were observed when substrates 1d and 1e, which
had no methoxy substitutions, were treated with TFA and thiourea
in 2 h (Table 3, entries 4 and 5).
Ph
S
O
PhCOCH2Cl
67
80
6
O
6d
NO
2
NO
2
OCH
3
S
5
6
Trace
Hydrolysis of S-alkylisothiouronium salts in aqueous alkali is a
simple and well established route to prepare the corresponding
alkylthiols.8 The mixture of 1a, TFA, and thiourea was subjected
to the NaOH-promoted hydrolysis to explore the tandem cycliza-
tion/nucleophilic addition/Hydrolysis reaction. After heating for
2 h, EtOAc was added to the mixture, and the upper organic phase
was collected and purified through column to give 2 in 95% yield.
Meanwhile, the bottom residue was treated with 1 M NaOH and
4-methoxylbenzylthiol 5 was obtained. At the same time a small
amount of dimmer product 4 was obtained as a pale powder since
thiol 5 was easily trapped by itself to form a disulfide (Fig. 3).
After 1 M NaOH solvent was proved to be the effective aqueous
alkali in generating the thiolate anion by decomposing isothiouro-
nium TFA salts, we further invested the coupling between the thio-
late anion and electrophiles to yield asymmetric dialky sulfides.
We tried the tandem cyclization/nucleophilic addition/hy-
drolysis/nucleophilic substitution reaction with organohalogens
as the electrophiles,9 and the results are shown in Table 4. 1-Bro-
mo-butane, 1-bromo-heptane, allylic bromide, and chlorinated
alkene were transferred to asymmetric thioesters 6 in medium
yields after 6 h at 50 °C, and disulfide 4 was also separated in
6–11% yields. Thiol 5 was not detected after the transformation
(entries 1–4). To our surprise, when an aryl fluoride such as
1-fluoro-2-nitro-benzene was subjected to the transformation,
the phenyl benzyl thioester was obtained in 80% yield after 6 h
at 50 °C and only trace amount of disulfide 4 was observed (entry
5). When 4-bromo-2-fluoro-1-nitro-benzene was subjected the
reaction to compare the reaction selectivity between fluoride and
bromide, only fluoride was substituted by thiol 5 to give 4-bro-
mo-2-(4-methoxy-benzylsulfanyl)-1-nitro-benzene in 78% yield,
and again trace disulfide 4 was detected (entry 6).
F
6e
NO2
NO
Br
2
OCH3
S
78
Trace
F
Br
6f
a
Conditions: 1a (0.2 mmol), TFA (0.1 mL), thiourea (0.2 mmol), 80 °C; then 1 M
NaOH, R–X (0.2 mmol), 50 °C, 6 h.
b
Isolated yield based on 1a.
NHCOCOOEt
NO
Br
2
S
TFA, SC(NH ) , then 1M NaOH,
2
2
S
Br
S
N
4-Bromo-2-Fluoro-1-nitro-benzene
+
COOEt
Br
OCH
7
6f
8
3
OCH
3
.
O
1 SnCl 2H O, EtOAc, rt
2 ClCOCOOEt, Py. DCM
2
2
N
S
N
HN
N
N
OCH
3
SR6494
Scheme 1. Access to the key intermediate of SR6494.
biological evaluation in our lab. Based on the synthesis of 6f, we
tested a new synthetic methodology to prepare 6-bromo-benzoth-
iazole-2-carboxylic acid ethyl ester 8 (Scheme 1), which is the key
intermediate of SR6494. 8 was obtained10 through a tandem
cyclization/nucleophilic addition/hydrolysis/nucleophilic substitu-
tion reaction started from thioformanilides 7, which could be
obtained via two steps including nitro reduction and amide forma-
tion. Continuous preparation of 8 in a gram scale was preliminarily
investigated and the results suggested that the benzyl group linked
to S atom was recyclable (Supporting information for detail).
SR6494, a promising ROCK inhibitor for the treatment of glau-
coma, exhibited excellent biochemical and cellular potencies
(IC50 = 0.4 nM and 6 nM, respectively) and over 100-fold ROCK/
PKA selectivity.6 A large amount of SR6494 was needed for further
COOEt
Conclusion
NHCOCOOEt
TFA, SC(NH2)2
N
S
+
O
O
+
S
then 1M NaOH
S
SH
OCH3
We developed a metal-free and recyclable procedure for ben-
zothiazoles. In this new synthetic methodology, odor-free and
cheap thiourea was used as a sulfur surrogate. Two types of valu-
able chemicals including benzothiazoles and asymmetric disulfides
2
1a
2
4
5
Figure 3. Tandem cyclization/nucleophilic addition/hydrolysis.
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4
Y. Yin et al. / Tetrahedron Letters xxx (2015) xxx–xxx
7. Matoba, M.; Kajimoto, T.; Node, M. Synlett 2007, 1930–1934.
8. Luzzio, F. A. Synth. Commun. 1984, 14, 209–214.
could be obtained in one reaction through the tandem cyclization/
nucleophilic addition/hydrolysis/nucleophilic substitution reaction
starting from thioformanilides. Meanwhile, asymmetric disulfides
could further transform to benzothiazoles through nitro reduction
and amide formation. In the preparation of the key intermediate of
SR6494, this synthetic route fully displayed its time saving, cost
efficient, and environmental friendly advantages. Preparation of
newly designed benzothiazole-based ROCK inhibitors by this novel
method is underway in our lab and will be published in due course.
9. Typical procedure: The mixture of 1a (0.2 mmol), TFA (0.1 mL), and SC(NH2)2
(0.2 mmol) was heated at 80 °C. After the reaction was complete (detected by
TLC), the mixture was cooled to room temperature and EtOAc (2 mL Â 2) was
added. The upper organic phase was evaporated and purified through column
to give 2 in 95% yield. Meanwhile, the bottom residue was stirred with 1 M
NaOH (1 mL) and R–X (0.2 mmol) at 50 °C for 6 h. After the reaction was
complete (detected by LC–MS), the mixture was extracted with EtOAc, washed
with brine, dried over Na2SO4, and concentrated under reduced pressure to
give a residue. The residue was purified through column to give asymmetric
disulfide 6. Benzothiazole-2-carboxylic acid ethyl ester (2): white solid; mp 58–
59 °C; 1H NMR (400 MHz, CDCl3) d = 8.20–8.18 (m, 1H), 7.92–7.90 (m, 1H),
7.54–7.47 (m, 2H), 4.49 (q, J = 6.8 Hz, 2H), 1.43 (t, J = 6.8 Hz, 3H); IR (KBr,
cmÀ1): 2926, 2853, 1741, 1716, 1498, 1293, 1095, 763, 730. Butylsulfanylmethy-
4-methoxy-benzene (6a): white solid; mp 73–74 °C; 1H NMR (400 MHz,
CDCl3) = 7.25 (d, J = 8.5 HZ, 2H), 6.87 (d, J = 8.5 HZ, 2H), 3.82 (s, 2H), 2.43 (t,
J = 7.5 HZ, 2H), 1.56 (m, 2H), 1.39 (m,2H), 0.91(t, J = 7.5 HZ, 3H); IR (KBr, cmÀ1):
2955, 2930, 2833, 1610, 1511, 1464, 1301, 1249, 1174, 1106, 1035, 830, 742,
545. 1-Heptyl sulfanylmethyl-4-methoxy-benzene (6b): white solid; mp 84–
85 °C; 1H NMR (400 MHz, CDCl3) d = 7.25 (d, J = 8.5 HZ, 2H) 6.87 (d, J = 8.5 HZ,
2H), 3.82 (s, 3H), 3.68 (s, 2H), 2.42 (t, J = 7.5 HZ, 2H), 1.58 (m, 2H), 1.37–1.28 (m,
8H), 0.90 (t, J = 6.5HZ, 3H); IR (KBr, cmÀ1): 3000, 2954, 2925, 2853, 1610, 1511,
1464, 1377, 1249, 1174, 1106, 1036, 828, 735, 670, 546. 4-Bromo-2-(4-
methoxy-benzylsulfanyl)-1-nitro-benzene (6c): colorless oil 1H NMR (400 MHz,
CDCl3) d = 7.24 (d, J = 6.0 HZ, 2H) 6.93 (d, J = 6.0 HZ, 2H) 5.98–5.89 (m, 1H)
5.50–5.36 (m, 2H) 3.99–3.93 (m, 2H) 3.83 (s, 3H), 3.45–3.41 (m, 1H) 3.30–3.26
(m, 1H); IR (KBr, cmÀ1): 3002, 2907, 2833, 1609, 1511, 1301, 1248, 1174, 1106,
1035, 990, 917, 833, 740, 674, 545. 2-(4-Methoxy-benzylsulfanyl)-1-phenyl-
ethanone (6d): white solid; mp 52–53 °C;1H NMR (400 MHz, CDCl3) d = 7.96 (d,
J = 7.5 HZ, 2H), 7.61–7.58 (m, 1H) 7.48 (d, J = 7.5 HZ, 2H), 7.28 (d, J = 8.5 HZ, 2H),
6.87 (d, J = 8.5 HZ, 2H), 3.82 (s, 3H), 3.74 (s, 2H), 3.69 (s, 2H); IR (KBr, cmÀ1):
2927, 1672, 1511, 1447, 1277, 1249, 1175, 1032, 833, 688. 1-Benzylsulfanyl-2-
nitro-benzene (6e): yellow solid; mp 109–110 °C; 1H NMR (400 MHz, CDCl3)
d = 8.22–8.20 (m, 1H), 7.54–7.52 (m, 1H), 7.50–7.45 (m, 1H), 7.33 (d, J = 8.0 Hz,
2H), 7.28–7.23 (m, 1H), 6.87 (d, J = 8.0 Hz, 2H), 4.16 (s, 2H), 3.80 (s, 3H); IR (KBr,
cmÀ1): 3086, 2830, 1506, 1334, 1304, 1248, 1176, 1028, 736, 654, 541; 13C
NMR (100 MHz, CDCl3) 159.18, 155.52, 138.07, 133.55, 130.28, 126.89, 126.84,
126.07, 124.62, 114.23, 55.39, 37.00; LC/MS (M+H+) (m/z) 276; HRMS (ESI-
Orbitrap) calcd for C14H14NO3S [M+H+]: 276.0694, found 276.0706. 4-Bromo-2-
(4-methoxy-benzylsulfanyl)-1-nitro-benzene (6f): yellow solid; mp 137–138 °C;
1H NMR (400 MHz, CDCl3) d = 8.12–8.10 (m, 1H) 7.63–7.62 (m, 1H) 7.40–7.38
(m, 1H) 7.35 (d, J = 6.4 Hz, 2H) 6.91 (d, J = 6.4 Hz, 2H) 4.17 (s, 2H) 3.83 (s, 3H);
IR (KBr, cmÀ1): 3107, 2966, 2919, 2359, 1581, 1503, 1327, 1250, 1110, 1030,
750, 672, 527.
Acknowledgments
The work was supported by Science and Technology Commis-
sion of Shanghai Municipality (Grant no. 12ZR1431100) and
National Natural Science Foundation of China (No. 21172148).
Support from Prof. Gang Zhao and Prof. Guanjun Wang was also
greatly appreciated.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.02.
054.
References and notes
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10. 6-Bromo-benzothiazole-2-carboxylic acid ethyl ester (8). white solid; mp 55–
56 °C; 1H NMR (400 MHz, CDCl3) d = 8.13–8.09 (m, 2H), 7.88–7.60 (m, 1H), 4.56
(q, J = 6.0 Hz, 2H) 1.50 (t, J = 6.0 Hz, 3H); IR (KBr, cmÀ1): 3089, 2981, 1741,
1715, 1497, 1316, 1102, 814, 759, 744, 522; 13C NMR (100 MHz, DMSO) 160.32,
158.99, 151.96, 138.26, 130.84, 126.56, 124.66, 121.78, 63.33, 14.26; LC/MS
(M+H+) (m/s): 286; HRMS (ESI-Orbitrap) calcd for C10H9BrNO2S [M+H+]:
285.9537, found 285.9556.
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Please cite this article in press as: Yin, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.02.054