DDQ-promoted C-S bond formation: Synthesis of 2-aminobenzothiazole derivatives under transition-metal-, ligand-, and base-free conditions

Article abstract of DOI:10.1055/s-0031-1291159

A transition-metal-free method for the intramolecular S-arylation of o-halobenzothiaoureas via DDQ-mediated leading to the 2-aminobenzothiazole derivatives is reported. The reactions are performed at room temperature under ligand- and base-free conditions with good to excellent yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291159

LETTER
▌1643
lDettDer Q-Promoted C–S Bond Formation: Synthesis of 2-Aminobenzothiazole
Derivatives under Transition-Metal-, Ligand-, and Base-Free Conditions
Synthesis of 2-Aminobenzothiazole Derivatives
Rui Wang,*a Wen-juan Yang,a Liang Yue,a Wei Pan,a Hong-yao Zengb
a
School of Pharmacy & Bioengineering, Chongqing University of Technology, Chongqing 400054, P. R. of China
Fax +86(23)62563182; E-mail: wangrx1022@163.com
b
Department of Chemistry and Life Sciences, Leshan Normal University, Leshan 614000, P. R. of China
Received: 07.03.2012; Accepted after revision: 16.04.2012
Herein we report a practical, cheap, and highly efficient
Abstract: A transition-metal-free method for the intramolecular S-
coupling reaction mediated by 2,3-dichloro-5,6-dicyano-
arylation of o-halobenzothiaoureas via DDQ-mediated leading to
benzoquinone (DDQ) without using any transition metal,
base, and ligand (this work in Scheme 1).
the 2-aminobenzothiazole derivatives is reported. The reactions are
performed at room temperature under ligand- and base-free condi-
tions with good to excellent yields.
previous work
X
Key words: 2-aminobenzothiazoles, transition-metal-free, ligand-
free, DDQ, S-arylation
S
[M]/ligand
R1
R2
base
N
H
N
H
path a
NH2
2-Aminobenzothiazoles, an important topical benzothia-
zole scaffold, are broadly found in bioorganic and medic-
inal chemistry1 with applications in drug discovery and
development for the treatment of various diseases, such as
diabetes,2 epilepsy,3 and tuberculosis.4 Therefore, much
attention has been paid to the development of efficient
methods for preparing 2-aminobenzothiazole derivatives.
Recent strategies for the synthesis of 2-aminobenzothia-
zoles based on transition-metal-catalyzed reactions nicely
complement the traditional synthetic approaches – the ox-
idative cyclization of thiobenzanilides.5 The transition-
metal-catalyzed, particularly palladium or copper, even
N
S
[M]/ligand
base
R1
R1
NHR2
R2NCS
+
X
path b
H
S
R1
[Pd]
R2
MnO2
N
H
N
H
path c
this work
R1
X
S
N
S
DDQ
R1
NHR2
iron,
intramolecular
cyclization
of
2-
R2
halobenzothiaoureas6a–d that were generated in situ or pre-
synthesized from suitable isothiocyanates and 2-haloani-
lines, and tandem addition–C–S coupling6e–i are the most
common and efficient methods (path a and path b in
Scheme 1). On the other hand, recent advances in the met-
al-mediated C–H functionalization provide a complemen-
tary and potentially more efficient methodology to
heteroaromatic compounds, because additional preactiva-
tion steps can be avoided (path c in Scheme 1).6j However,
using excess amounts of toxic reagents or transition met-
als is a major drawback of these methods. Moreover the
high cost of palladium and the required especially suitable
ligands, as well as the stoichiometric base and low func-
tional-group tolerance, led to a need to explore the more
practical approaches for such coupling reactions. There-
fore, in order to avoid the use of transition metals, the de-
velopment of new efficient strategy appears very
appealing in view of so-called green and sustainable
chemistry.
N
H
N
H
Scheme 1 Comparison of previous works with this work
Our initial investigations were carried out using a series of
oxidants for the model reaction of 2-iodobenzothiaourea
1a, which can easily be synthesized by the reaction of
commercially available 2-iodoaniline and phenyl isothio-
cyanate.7 To our delight, experimental data showed that
the DDQ could promote the reaction more effectively than
other types of oxidants, with conversions of up to 61% af-
ter 24 hours under transiton-metal-free, ligand-free, and
base-free reaction conditions at room temperature (Table
1, entry 1). However, only a trace amount of 2a was de-
tected when inorganic oxidants were used instead of
DDQ, such as K2S2O8, CAN, Ag2O, CAN/H2O2,8 I2, and
KBrO3 were no longer the effective oxidants in the reac-
tion, and no desired 2a was isolated under transiton-met-
al-free, ligand-free, and base-free reaction conditions at
room temperature (Table 1, entries 2–4). Meanwhile, re-
placing DDQ with stronger oxidant, KMnO4/SiO2,9 only
the intermediate of o-iodobenzothiaourea was detected,
the use of Dess–Martin periodinane10 resulted in a much
lower reaction efficiency (Table 1, entries 5 and 6). Based
SYNLETT 2012, 23, 1643–1648
Advanced online publication: 11.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291159; Art ID: ST-2012-W0196-L
© Georg Thieme Verlag Stuttgart · New York

1644
R. Wang et al.
LETTER
tional groups including electron-donating (Me and OMe)
and electron-withdrawing (NO2 and CF3) substituents
even halogens (F and Cl, Table 2, entries 13–18) were tol-
erated well. In the case of the electronic nature of the aro-
matic motifs, such as 4-methyl-o-iodoaniline, containing
an electron-donating substituent, increased yields of prod-
ucts were obtained, and the effect is the reverse as with
electron-withdrawing substituents.
Table 1 Screening Conditions for the Synthesis of 2-Aminobenzo-
thiazolea
I
N
S
S
NHPh
Ph
N
N
H
H
1a
2a
Entry
Oxidant
Solvent
Yield (%)b
For aryl iodides, we were pleased to find that the electron-
ic nature of the phenyl isothiocyanate moiety seems to
have little influence on the reaction, which is evident from
the fact that a variety of substituents, such as Me, OMe,
NO2, Cl, or Br can give satisfactory results. It is worth not-
ing that C–Br or C–Cl compatible with reaction condi-
tions are particularly appealing, since these substituents
offer great opportunity for further preparing more com-
plex 2-substituted benzothiazoles by further operations
(Table 2, entries 5, 6, 9, and 10).
1
2
DDQ
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
61
K2S2O8/CAN/Ag2O
trace
trace
trace
n.d.
<50
trace
78
c
3
CAN/H2O2
4
I2/KBrO3
d
5
KMnO4/SiO2
6
DMPe
DDQ
DDQ
DDQ
DDQ
DDQ
7
In addition, 2-alkyl aminobenzothiazole can also be ob-
tained in good yield (Table 2, entry 22). The requirement
for an ortho-halo-substituted precursor could be eliminat-
ed through a direct cyclization using anilines as aryl-alkyl
thiaoureas provided another access to 2-aminobenzothia-
zoles. Whereas it is important to note that this methodol-
ogy could not be applied to the aryl isothiocyanate
substrates, two isomers were observed (Table 2, entry 23).
As far as aryl isothiocyanate substrates are concerned, us-
ing aryl iodides, which act as directing group, could avoid
the formation of isomers.
8
DMF
9
DMSO
DMSO
DMSO
92
10
11
86f
80g
a Reaction conditions: o-iodobenzothiaourea (1a, 1.0 mmol), oxidant
(1.2 mmol), solvent (3.0 mL), r.t.
b Yield of isolated product after column chromatography.
c Conditions: 30% aq H2O2 (4 equiv) and CAN (0.1 equiv).
d KMnO4/SiO2 (0.90 g, 2.5 mmol) was added.
e Dess–Martin periodinane.
f Conditions: DDQ (1.5 mmol).
When 1,1-diphenylethylene or TEMPO, which are both
known to be effective radical scavengers, was added to the
reaction mixture, the reaction progress was significantly
decreased under the present DDQ-promoted C–S bond-
forming process, and only poor product yields were ob-
tained, even after longer reaction times (48 h, yield
<20%), suggesting that our present oxidative C–S bond-
forming reaction involves radical intermediates. Howev-
er, further studies are needed to unambiguously establish
the reaction mechanism. A tentative mechanism for the
coupling is proposed in Scheme 2. A single electron trans-
fer from the aryl thiaoureas to DDQ generates a radical
cation and a DDQ radical anion. The anionic oxygen of
DDQ radical anion then abstracts the hydrogen cation
from the radical cation and generates sulfanyl radical B.
Subsequently, Oxidation of an intermediate cyclohexadi-
enyl radical C can occur by electron transfer (ET) to give
a cyclohexadienyl cation, followed by proton transfer
(PT) gives 2-aminobenzothiazole derivatives. This result
does not exclude an alternative pathway, which involves
C–H bond cleaving hydrogen radical abstraction (HRA)
as a single-step transformation.
g Conditions: DDQ (1.0 mmol).
on these promising initial results we decided to further op-
timize the reaction conditions, especially improving the
solubility of the intermediates o-iodobenzothiaourea. Fur-
ther optimization of these preliminarily obtained condi-
tions showed that the solvent DMSO was far more
superior to DMF, affording 2a in 92% yield even under
room temperature (Table 1, entries 8 and 9) and proved to
be the solvent of choice. Furthermore, both increase and
decrease the amount of DDQ and reduced the yield (Table
1, entries 10 and 11). Only o-iodobenzothiaourea was de-
tected without DDQ.
With the optimized conditions in hand, the generality of
this transformation was examined by using various o-
halobenzothiaoureas, and the corresponding results are
listed in Table 2. This method is efficient for the synthesis
of a number of 2-aminobenzothiazole derivatives in good
to excellent yields. The nature of the ortho-substituted
halogen on the aniline moiety was very important to the
reaction outcome. (o-Iodoaryl)thiaoureas or (o-bromo-
aryl) thiaoureas can smoothly be converted into the de-
sired products in synthetic acceptable to excellent yields,
however, the use of o-chloro-substituted substrates to ef-
fect such transformations proved unsuccessful under
these conditions that probably attributed to their poorer
tendency to leave than their iodo or bromo analogues (Ta-
ble 2, entries 1–3). Regarding the R1 moiety, several func-
In summary, we have successfully developed a straight-
forward, high efficient, and mild DDQ-promoted method
for the intramolecular S-arylation providing 2-aminoben-
zothiazole ring system derivatives under transition-metal-,
ligand-, and base-free conditions. In the near future we
would like to establish another methodology for this trans-
formation under transition-metal-free conditions.
Synlett 2012, 23, 1643–1648
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Aminobenzothiazole Derivatives
1645
–O
CN
SH+
DDQ
CN
Cl
+
1t
N
N
H
O
N
Cl
A
O
CN
CN
Cl
S
H
N
+
S
N
N
Cl
H
H
C
B
OH
–O
CN
H
PT
S
N
ET
H
CN
Cl
Cl
+
N
OH
CN
Cl
O
or
H
S
N
HRA
H
+
N
CN
OH
Cl
OH
OH
Cl
CN
CN
S
H
N
+
N
Cl
2t
Scheme 2 Proposed reaction mechanism
Table 2 Effect of Substituents on 2-Aminobenzothiazoles Formationa
X
S
N
S
DDQ (1.2 equiv)
DMSO, r.t.
R1
R1
NHR2
R2
N
N
H
H
1
2
Entry
1
Substrate
Product
Yield (%)b
92
S
N
I
H
N
S
N
H
N
H
2a
2a
2a
2b
2c
2d
S
N
Br
H
N
S
S
S
S
S
2
3
4
5
6
74
–
N
H
N
H
S
N
Cl
H
N
N
H
N
H
S
N
I
H
N
88
89
90
N
H
N
H
S
N
I
Cl
Br
H
N
Cl
Br
N
H
N
H
S
N
I
H
N
N
H
N
H
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1643–1648

1646
R. Wang et al.
LETTER
Table 2 Effect of Substituents on 2-Aminobenzothiazoles Formationa (continued)
X
S
N
S
DDQ (1.2 equiv)
DMSO, r.t.
R1
R1
NHR2
R2
N
N
H
H
1
2
Entry
7
Substrate
Product
Yield (%)b
S
N
I
H
N
S
95
N
H
N
H
2e
2f
S
N
I
O
H
N
S
O
8
9
88
92
95
92
95
83
N
H
N
H
S
N
I
Cl
H
N
S
Cl
Br
N
H
N
H
2g
S
N
I
Br
H
N
S
10
11
12
13
N
H
N
H
2h
O
S
N
O
I
H
S
N
N
H
N
H
2i
S
N
I
H
N
S
N
H
N
H
2j
F
S
F
I
H
S
N
N
N
H
N
H
2k
F
S
N
F
I
H
N
S
S
14
15
16
17
18
80
89
84
86
88
N
H
N
H
2l
F
S
N
F
I
H
N
NO2
N
H
N
H
2m
Cl
S
Cl
I
H
S
N
N
N
H
N
H
2n
S
N
I
H
N
S
S
Cl
Cl
Cl
N
H
N
H
2o
S
I
F
H
N
F
N
Cl
N
H
N
H
2p
Synlett 2012, 23, 1643–1648
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Aminobenzothiazole Derivatives
1647
Table 2 Effect of Substituents on 2-Aminobenzothiazoles Formationa (continued)
X
S
N
S
DDQ (1.2 equiv)
DMSO, r.t.
R1
R1
NHR2
R2
N
N
H
H
1
2
Entry
19
Substrate
Product
Yield (%)b
81
F3C
S
N
F3C
F3C
F3C
I
H
N
S
S
S
N
H
N
H
2q
F3C
S
N
I
O
H
N
O
20
21
22
77
86
92c
N
H
N
H
2r
F3C
S
N
I
NO2
H
N
NO2
N
H
N
H
2s
2t
S
N
H
N
S
N
N
H
H
S
N
H
N
S
23
96d
S
N
H
N
H
H
N
N
a Reaction conditions: o-halobenzothiaoureas 1 (1.0 mmol), DDQ (1.2 mmol), DMSO (3.0 mL), r.t., 24 h.11
b Yield of isolated product after column chromatography.
c Reaction time: 36 h.
d Product obtained as an 55:45 ratio of regioisomers as determined by 1H NMR and (LC–MS) spectroscopic analysis of the unpurified reaction
mixture.
(6) For metal-catalyzed intramolecular cyclizations of 2-
Acknowledgment
halobenzothioureas, see: (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.
We are grateful to the National Natural Science Foundation of Chi-
na (31170747) and Chongqing City Natural Science Foundation of
China (No.cstc2011jjA10088) for financial support.
Tetrahedron Lett. 2008, 49, 467. (d) Benedí, C.; Bravo, F.;
Uriz, P.; Fernandez, E.; Claver, C.; Castillon, S. Tetrahedron
Lett. 2003, 44, 6073. Tandem addition–C–S coupling
References and Notes
reaction: (e) Pi, S.-S.; Zhang, X.-G.; Tang, R.-Y.; Li, J.-H.
Synlett 2009, 3032. See also: (f) Ding, Q. P.; He, X.-D.; Wu,
J. J. Comb. Chem. 2009, 11, 587. See also: (g) Qiu, J.;
Zhang, X.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Adv. Synth.
Catal. 2009, 351, 2319. See further: (h) Guo, Y.; Tang, R.-
Y.; Zhong, P.; Li, J.-H. Tetrahedron Lett. 2010, 51, 649. See
also: (i) Ding, Q. P.; Cao, B. P.; Liu, X. J.; Zong, Z.-Z.;
Peng, Y. Y. J. Green Chem. 2010, 12, 1607. (j) Oxidative
C–H bond functionalization: Joyce, L. L.; Batey, R. A. Org.
Lett. 2009, 11, 2792.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1643–1648

1648
R. Wang et al.
LETTER
(9) Mohammadpoor-Baltork, I.; Ali Zolfigolb, M. A.;
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(11) Typical Procedure
J = 8.4 Hz, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.40 (d, J = 8.8
Hz, 2 H), 7.57 (d, J = 8 Hz, 2 H), 7.80 (d, J = 10 Hz, 2 H),
10.62 (br, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ =
119.6, 119.8, 121.6, 123.0, 125.8, 126.4, 129.3, 130.5,
140.0, 152.4, 161.7 ppm. ESI-HRMS: m/z calcd for
[C13H9ClN2S + H]+: 260.0175; found: 260.0183.
To a solution of (o-iodoaryl) thiaoureas (1.0 mmol) in
DMSO (3 mL) were added DDQ in five equal portions. The
mixture was stirred at r.t. for 24 h (TLC monitoring). After
the reaction was completed, H2O (10 mL) and a sat. aq
NaHCO3 solution (5 mL) were added, and then the aqueous
solution was extracted with EtOAc (3 × 15 mL). The
combined organic extracts were dried over anhyd Na2SO4
and concentrated, and then the residue was purified by
column chromatography [eluent: PE–EtOAc (5:1 to 7:1)] on
silica gel to provide the desired product.
Compound 2h: 1H NMR (400 MHz, DMSO-d6): δ = 2.35 (s,
3 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.49–7.54 (m, 3 H), 7.62 (s,
1 H), 7.79 (d, J = 8.8 Hz, 2 H), 10.53 (br, 1 H) ppm. 13
C
NMR (100 MHz, DMSO-d6): δ = 21.3, 113.5, 119.5, 119.9,
121.5, 127.5, 130.5, 132.1, 132.3, 10.5, 150.3, 160.9 ppm.
ESI-HRMS: m/z calcd for [C14H11BrN2S + H]+: 318.9905;
found: 318.9937.
Compound 2t: 1H NMR (400 MHz, CDCl3): δ = 1.15–1.41
(m, 5 H), 1.51–1.56 (m, 1 H), 1.67–1.73 (m, 2 H), 2.05–2.30
(m, 2 H), 2.66–2.69 (m, 1 H), 3.50 (br s, 1 H), 6.99 (t, J = 2.4,
9.3 Hz, 1 H), 7.27 (dd, J = 2.4, 7.8 Hz, 1 H), 7.42 (dd,
J = 4.9, 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
24.7, 25.5, 33.5, 57.6, 121.1, 121.3, 123.6, 128.9, 136.9,
152.4, 165.7 ppm. ESI-HRMS: m/z calcd for [C13H16N2S +
H]+: 233.1112; found: 233.1140.
Compound 2a: 1H NMR (400 MHz, CDCl3): δ = 7.16–7.18
(m, 2 H), 7.33 (t, J = 7.3 Hz, 1 H), 7.40 (t, J = 8.3 Hz, 2 H),
7.50 (d, J = 7.7 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.63 (d,
J = 7.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
119.5, 120.0, 120.8, 122.6, 124.3, 126.2, 129.6, 130.0,
139.7, 151.4, 164.1 ppm. ESI-HRMS: m/z calcd for
[C13H10N2S + H]+ : 227.0643; found: 227.0649.
Compound 2c: 1H NMR (400 MHz, DMSO-d6): δ = 7.14 (t,
Synlett 2012, 23, 1643–1648
© Georg Thieme Verlag Stuttgart · New York

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