Direct transition metal-free C-S bond formation: Synthesis of 2-aminobenzothiazole derivatives via base-mediated approach

Article abstract of DOI:10.1016/j.tetlet.2012.06.034

A general, efficient, and more practical protocol for the base-mediated intermolecular or intramolecular S-arylation leading to the 2-aminobenzothiazole derivatives is reported. Remarkably, all reactions were carried out under transition-metal-free conditions with good to excellent yields, rendering the methodology presented herein highly valuable from both environmental and economic points of view.

Full text of DOI:10.1016/j.tetlet.2012.06.034

Tetrahedron Letters 53 (2012) 4529–4531
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct transition metal-free C–S bond formation: synthesis
of 2-aminobenzothiazole derivatives via base-mediated approach
Rui Wang a, , Zhi Chen b, Liang Yue a, Wei Pan a, Jun-Jie Zhao a
⇑
a School of Pharmacy & Bioengineering, Chongqing University of Technology, Chongqing 400054, China
b School of Chemical Engineering, Chongqing University of Technology, Chongqing 400054, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general, efficient, and more practical protocol for the base-mediated intermolecular or intramolecular
S-arylation leading to the 2-aminobenzothiazole derivatives is reported. Remarkably, all reactions were
carried out under transition-metal-free conditions with good to excellent yields, rendering the method-
ology presented herein highly valuable from both environmental and economic points of view.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 March 2012
Revised 31 May 2012
Accepted 8 June 2012
Available online 15 June 2012
Keywords:
2-Aminobenzothiazoles
Transition metal-free
Base
DABCO
S-Arylation
The 2-N-substituted benzothiazoles are attractive synthetic tar-
gets, primarily due to the range of antidiabetic, antibacterial, and
anticancer properties associated with them.1 Due to their broad
spectrum of biological activity, these compounds have received a
great deal of attention in connection with their synthesis. In recent
years, classical methods for the synthesis of 2-aminobenzothiazoles
have been supplanted by transition metal-catalyzed methodology
in which the palladium, copper, or iron was used as catalyst
(Scheme 1, path a).2 Particularly several one-pot procedures by
the reactions of o-iodoaniline with isothiocyanate have been re-
ported (Scheme 1, path b). Among the different catalysts, inexpen-
sive and nontoxic iron provided the efficient and straightforward
means for this transformation, meanwhile, circumventing the need
for intermittent isolation and purification.3
Although many of the known strategies for 2-aminobenzothia-
zole synthesis provide the products in good yield, these methods
are still using transition metal catalysts, which may possibly leave
toxic traces of metals in the products. Therefore, in order to avoid
the use of transition metals, the development of new efficient and
nonmetallic method for the synthesis of 2-aminobenzothiazoles
appears very appealing in view of so-called green and sustainable
chemistry. Along these lines, the first breakthrough metal-free
intramolecular C–S bond formation using Cs2CO3 as base was
uncovered by Liu and co-workers (Scheme 1, path c),4 however,
prefunctionalized substrates were needed and when R2 = aryl, it
gave low yields. Based on the high electrophilicity of isothiocya-
nates, we envisaged that directed intermolecular carbon–sulfur
bond formation would be possible if suitable base was selected
to increase the nucleophilicity of 2-halobenzothioureas.
With this idea in mind, we initiated our study by testing various
conditions for the reaction of o-iodoaniline with phenyl isothiocy-
anate in the presence of base (Table 1). After a series of experi-
ments, we found that organic base (DBU, DABCO) showed higher
reactivity than inorganic base (K2CO3, K3PO4, LiOtBu, NaOtBu, and
Previous works
X
R1
S
N
S
path a
R1
R1
NHR2
NHR2
R2
N
H
NH2
N
H
d] or [Cu]
[P
N
path b
R1
R1
+
R2NCS
R2
[Cu] or [Fe]
Ligand/base
S
X
X
S
N
path c
R1
NHR2
NHR2
Cs2CO3
S
N
H
N
H
when R2 = aryl, yields < 62%
This design
R1
NH2
N
S
base
R1
+
R2NCS
?
X
R2 = aryl and alkyl
⇑
Corresponding author. Tel./fax: +86 23 6256 3182.
E-mail address: wangrx1022@163.com (R. Wang).
Scheme 1. Comparison of previous works with our design.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.034

4530
R. Wang et al. / Tetrahedron Letters 53 (2012) 4529–4531
Table 1
Table 2
Synthesis of 2-aminobenzothiazoles under different conditionsa
Base-mediated C–S bond formationa
NH2
Entry
3a
Product
Method
A
Yieldb,c (%)
91(47)
N
base
H
N
SCN
+
N
H
N
S
3a
I
1a
2a
S
N
Entry
Base
Temp (°C)
Time (h)
Yieldb (%)
H
N
3b
3c
3d
3e
3f
A
B
B
B
A
B
B
74(33)
93(50)
93(47)
94(49)
92(49)
96(51)
90(50)
1
2
3
4
5
6
7
8
K2CO3
K3PO4
110
110
110
110
110
110
130
130
130
130
130
110
110
110
130
24
24
24
24
24
24
4
4
6
6
6
57
62
71
75
S
N
LiOtBu
NaOtBu
KOtBu
KOtBu
KOtBu
DABCOÁ6H2O
DABCO
Cs2CO3
DBU
DABCO
DABCO
DABCO
DABCO
H
N
Cl
S
N
79
68c
H
N
Br
84
79
91
47
86
50
55
55
S
N
9
H
N
10
11
12
13
14
15
NO2
S
6
N
H
N
24
48
6
S
N
56/60/40/22d
H
N
a
Br
3g
3h
Reaction conditions (unless otherwise noted): Under N2 protection, o-iodoani-
line (1.0 mmol) and phenyl isothiocyanate (1.2 mmol) were mixed and stirred for
1 h at room temperature, then anhydrous DMSO (5 ml) and base (3.0 mmol) were
DMSO = dimethylsulfoxide,
DBU = 1,8-diazabicyclo [5.4.0]undec-7-ene.
S
N
H
N
added.
DABCO = 1,
4-diazabicyclo[2.2.2]octane,
NO2
S
b
Isolated yield.
1,10-Phen (20 mol %) was added.
Reaction was carried out in DMF, dioxane, dibutylether, and toluene
O
S
N
c
H
N
3i
3j
3k
3l
A
A
B
C
89(45)
96(52)
97(52)
92(53)
d
respectively.
S
H
N
N
S
KOtBu). In general it appears that the yield of the target compound
is closely related to the basicity of the catalysts: strong basicity is
beneficial to the reaction (Table 1, entries 3–6), whereas mild basi-
city reduced the yield of the substituted 2-aminobenzothiazoles
(Table 1, entries 1–2). Further optimization of the standard reac-
tion parameters revealed that the reaction could be greatly accel-
erated at higher temperatures, providing 3a in higher yield and
with shorter reaction time (Table 1, entries 7–10). Recently, the
research groups of Shirakawa/Hayashi,5 Kwong/Lei,6 and Shi7 de-
scribed the base-promoted homolytic aromatic substitution, how-
ever, with 20 mol % organocatalyst-1,10-phenanthroline, it only
gave inferior results in our version probably attributed to the inter-
molecular polymerization (Table 1, entry 6). When using Cs2CO3 as
base, it only afforded 47% yield. Finally, DABCO was found to be the
most effective base for this transformation since it resulted in the
highest conversion to the desired product (Table 1, entry 9).
Probably, from the nucleophilic substitution reaction mechanism,
non-nucleophilic nitrogen containing strong base plays not only
base—abstract proton from thiol intermediate, but also assistor to
help halogen leave through protonated DABCO. To evaluate the sol-
vent effect, the reaction was carried out under similar reaction con-
ditions using various organic solvents such as DMF, toluene,
dioxane, and dibutylether. As shown in Table 1, DMSO provided
excellent yields and proved to be the solvent of choice, whereas
the use of other solvents resulted in lower yields of 3a (Table 1,
entry 15).
H
N
Br
N
F
S
H
N
N
S
F
H
N
3m
3n
3o
3p
3q
C
C
C
C
C
90(50)
88(51)
87(49)
94(55)
82(45)
N
Cl
S
H
N
N
S
Cl
H
N
N
F3C
F3C
S
H
N
N
S
H
N
NO2
N
S
N
H
B
C
50(27)
78(41)
N
3r
3s
S
N
H
N
B
C
55(29)
76(40)
a
b
c
Reaction conditions: see Ref. 9.
Isolated yield.
The reaction was carried out in the presence of Cs2CO3(2 equiv) and the yield of
We next investigated whether also other substrates undergo
highly efficient one-pot cyclization. For more activity substrates
(o-iodoaniline with electron-donating group and phenyl isothiocy-
anate with electron-withdrawing group), especially for phenyl iso-
thiocyanate with electron-withdrawing group, we found that 3c
was formed exclusively when the coupling-reaction mixture was
heated at the melting point of 4-chlorophenyl isothiocyanate for
one hour firstly and then anhydrous DMSO and DABCO were added
(Table 2, entry 3c, procedure B, see Ref. 9). Although for inactive
substrates (o-iodoaniline with electron-withdrawing group or/
isolated product is shown in parenthesis.
and phenyl isothiocyanate with electron-donating group), the
preparation of intermittent-o-halobenzothioureas which was
readily synthesized according to the reference method is required,8
we were pleased to find that this intramolecular cyclization could
be finished in excellent yields (Table 2, entry 11, procedure C, see

R. Wang et al. / Tetrahedron Letters 53 (2012) 4529–4531
4531
Ref.). Notably, under all three kinds of conditions, DABCO was
References and notes
found to be the most effective base for this transformation.
To further investigate the feasibility of this synthetic method for
preparing 2-aminobenzothiazole derivatives, a series of substrates
were examined. The results are summarized in Table 2. As shown
in Table 2, the presented methodology proved to be efficient for
the synthesis of a number of 2-aminobenzothiazole derivatives in
moderate to good yields. However, the electronic nature of the
substituents affected the reaction outcome in very different ways.
For instance, when using one-pot procedure (Methods A and B), for
isothiocyanates bearing electron-donating substituents were sub-
jected to the reaction under standard conditions, there was a lower
yield of the desired adducts formed (Table 2, entry 3b) and the ef-
fect was the reverse for the substrates bearing electron-withdraw-
ing substituents (Table 2, entries 3c–3e). On the contrary, the
presence of electron-donating substituents, such as methyl or
methoxy groups, in the aryl iodide coupling partner of the sub-
strates accelerated the coupling process and successfully furnished
the corresponding 2-aminobenzothiazoles in high yields (Table 2,
entries 3f–3k). Furthermore, completely opposite electronic nature
was observed when using o-iodobenzothioureas as starting mate-
rials (Method C): electron-donating substituents associated with
aryl iodide decreased the product yields and with electron with-
drawing groups increased the product yields. Comparatively, we
found that the electronic nature of the isothiocyanate moiety
seems to have little influence on the reaction, which is evident
from the fact that both the electron-rich and the electron-poor iso-
thiocyanates underwent the intramolecular coupling reaction effi-
ciently in good to excellent yields (Table 2, entries 3l–3q).
Particularly notable, alkyl o-iodobenzothioureas were also suitable
substrates in this process in good yields (Table 2, entries 3r–3s).
In summary, we have successfully developed a straightforward,
high efficient, and base-mediated method for intermolecular or
intramolecular S-arylation providing 2-aminobenzothiazole ring
system derivatives in the absence of transition-metal catalysts
and ligands. Compared with using Cs2CO3 as base, the approach
mediated by DABCO can be applied to wilder range of substrates:
not only to 2-alkylaminobenzothiazoles, but also to 2-aryl-
aminobenzothiazoles, more interestingly, for the substrates of o-
iodoaniline with electron-donating group and phenyl isothiocya-
nate with electron-withdrawing group we could use one-pot pro-
cedure. In the near future we would like to establish other
methodologies for this transformation under transition-metal-free
conditions.
1. (a) Hays, S. J.; Rice, M. J.; Ortwine, D. F.; Johnson, G.; Schwartz, R. D.; Boyd, D. K.;
Copeland, L. F.; Vartanian, M. G.; Boxer, P. A. J. Pharm. Sci. 1994, 83, 1425; (b)
Soneda, T.; Takeshita, H.; Kagoshima, Y.; Yamamoto, Y.; Hosokawa, T.; Konosu,
T.; Masuda, N.; Uchida, T.; Achiwa, I.; Kuroyanagi, J.; Fujisawa, T.; Yokomizo, A.;
Noguchi, T. WO2009084614, 2009.; (c) Aelterman, W.; Lang, Y.; Willemsens, B.;
Vervest, I.; Leurs, S.; DeKnaep, F. Org. Process Res. Dev. 2001, 5, 467–471.
2. Traditional synthetic methods: (a) Bose, D. S.; Idrees, M. Tetrahedron Lett. 2007,
48, 669; (b) Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71, 8261; (c) Downer-Riley,
N. K.; Jackson, Y. A. Tetrahedron 2008, 64, 7741; (d) Xian, H.; Jing, T. Tetrahedron
2003, 59, 4851; (e) Garin, J.; Melendez, E.; Merchan, F. L.; Merino, P.; Orduna, J.;
Tejero, T. Syn. Commun. 1990, 20, 2327. metal-catalyzed intramolecular
cyclization of 2-halobenzothioureas; (a) Joyce, L. L.; Evindar, G.; Batey, R. A.
Chem. Commun. 2004, 446; (b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71,
1802; (c) Wang, J.; Peng, F.; Jiang, J.; Lu, Z.; Wang, L.; Bai, J.; Pan, Y. Tetrahedron
Lett. 2008, 49, 467; (d) Benedí, C.; Bravo, F.; Uriz, P.; Fernandez, E.; Claver, C.;
Castillon, S. Tetrahedron Lett. 2003, 44, 6073.
3. Tandem addition/C–S coupling reaction: (a) Ding, Q. P.; He, X. D.; Wu, J. J. Comb.
Chem. 2009, 11, 587; (b) Qiu, J.; Zhang, X.; Tang, R. Y.; Zhong, P.; Li, J. H. Adv.
Synth. Catal. 2009, 351, 2319; (c) Guo, Y.; Tang, R.-Y.; Zhong, P.; Li, J. H.
Tetrahedron Lett. 2010, 51, 649; (d) Ding, Q. P.; Cao, B. P.; Liu, X. J.; Zong, Z.-Z.;
Peng, Y. Y. J. Green Chem. 2010, 12, 1607. Oxidative C–H Bond Functionalization;
(e) Joyce, L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792; (f) Wang, H. B.; Wang, L.;
Shang, J. S.; Li, X.; Wang, H. Y.; Gui, J.; Lei, A. W. Chem. Commun. 2012, 48, 76.
4. Feng, E. G.; Huang, H.; Zhou, Y.; Ye, D. J.; Jiang, H. L.; Liu, H. J. Comb. Chem. 2010,
12, 422.
5. Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
15537.
6. Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F.
Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737.
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J.; Shi, Z. J. Nat. Chem. 2010, 2, 1044.
8. (a) Baltabaev, U. A.; Makhsumov, A. G.; Zakirov, U. B.; Babaev, I. D.;
Shukurullaev, K. Pharm. Chem. J. 2002, 36, 77; (b) Belboukhari, N.; Cheriti, A.;
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N.; Narayanasamy, J. Tetrahedron Lett. 1993, 34, 6447.
9. General experimental procedure: o-iodoaniline (1.0 mmol) and phenyl
isothiocyanate (1.2 mmol) was mixtured and stirred for 1 h at room
temperature (Method A), or o-iodoaniline (1.0 mmol) and phenyl
isothiocyanate (1.2 equiv) was mixtured and stirred for 1 h at melting point
temperature of phenyl isothiocyanate (Method B), or o-halobenzothioureas
(1.0 mmol) (Method C), then anhydrous DMSO (5 ml) and base (3.0 mmol) was
added, the stirring continued for about 5–10 h at 130 °C (TLC monitor). After the
reaction was completed, the reaction mixture was cooled to room temperature
and ice-water was added, then the mixture was extracted with EtOAc. The
combined organic phase was dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under vacuum and then the residue was purified
by column chromatography (eluent: petroleum ether/ethyl acetate (5:1 to 7:1))
on silica gel to provide the desired product. Analytical data for some
representative compounds: Compound 3a: 1H NMR (400 MHz, CDCl3, ppm):
d = 7.16 (t, J = 7.2, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 8.4 Hz, 2H), 7.50 (d,
J = 7.8 Hz, 2H), 7.61 (dd, J1 = 13 Hz, J2 = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d = 119.5, 120.0, 120.8, 122.6, 124.3, 126.2, 129.6, 130.0, 139.7, 151.4, 164.1. ESI-
HRMS m/z calcd. For [C13H10N2S+H]+: 227.0643, found 227.0649. Compound 3c:
1H NMR (400 MHz, DMSO-D6, ppm): d = 7.14 (t, J = 8.4 Hz, 1H), 7.31 (t, J = 7.6 Hz,
1H), 7.40 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8 Hz, 2H), 7.80 (d, J = 10 Hz, 2H), 10.62
(br, 1H); 13C NMR (100 MHz, DMSO-D6) d = 119.6, 119.8, 121.6, 123.0, 125.8,
126.4, 129.3, 130.5, 140.0, 152.4, 161.7. ESI-HRMS m/z calcd. For
[C13H9ClN2S+H]+: 260.0175, found 260.0183. Compound 3d: 1H NMR
(400 MHz, DMSO-D6, ppm): d = 7.16 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H),
7.53 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.82(d,
J = 7.6 Hz, 1H), 10.64 (br, 1H); 13C NMR (100 MHz, DMSO-D6) d = 119.5, 121.4,
125.7, 127.5, 129.3, 130.5, 132.3, 140.1, 154.3, 161.0. ESI-HRMS m/z calcd. For
[C13H9BrN2S+H]+: 303.9670, found 303.09658. Compound 3g: 1H NMR
(400 MHz, DMSO-D6, ppm): d = 2.35 (s, 3H), 7.14 (d, J = 8.2 Hz, 1H), 7.49–7.54
(m, 3H), 7.62 (s, 1H), 7.79 (d, J = Hz, 2H), 10.53 (br, 1H). 13C NMR (100 MHz,
DMSO-D6) d = 21.3, 113.5, 119.5, 119.9, 121.5, 127.5, 130.5, 132.1, 132.3, 10.5,
150.3, 160.9. ESI-HRMS m/z calcd. For [C14H11BrN2S+H]+: 318.9905, found
318.9937. Compound 3r: 1H NMR (400 MHz, CDCl3, ppm): d = 1.15–1.41 (m,
5H), 1.51–1.56 (m, 1H), 1.67–1.73 (m,2H), 2.05–2.30 (m, 2H), 2.66–2.69 (m, 1H),
3.50 (br, s, 1H), 6.99 (t, J = 2.4, 9.3 Hz,1H), 7.27 (dd, J = 2.4, 7.8 Hz, 1H), 7.42 (dd,
J = 4.9, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d = 24.7, 25.5, 33.5, 57.6, 121.1,
121.3, 123.6, 128.9, 136.9, 152.4, 165.7. ESI-HRMS m/z calcd. For
[C13H16N2S+H]+: 233.1112, found 233.1140.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (31170747) and Chongqing City Natural Science Foundation
of China (No. cstc2011jjA10088) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.034. These data include MOL files and InChiKeys of the most
important compounds described in this article.