A new and efficient synthesis of 2-aminobenzothiazoles derivatives from o-nitroaniline

Article abstract of DOI:10.3184/174751913X13848836801606

A novel sy nthesis of 2-aminobenzothia zoles from a transition-met al-free reaction between aryl isothioc yanates and o-nitroaniline in the presence of K₂CO₃ is reported. The newly developed method is an efficient and cost-effective approach to synthesise 2-aminobenzothiazoles.

Full text of DOI:10.3184/174751913X13848836801606

778 RESEARCH PAPER
DECEMBER, 778–779
JOURNAL OF CHEMICAL RESEARCH 2013
A new and efficient synthesis of 2-aminobenzothiazoles derivatives from
o-nitroaniline
Behrooz Mirzaa*, Roghieh Mirzazadehb and Mohsen Zeeba
aDepartment of Applied Chemistry, Faculty of Science, Islamic Azad University, South Tehran Branch, Tehran, Iran
bDepartment of Biochemistry, Pasteur Institute of Iran, Tehran
A novel synthesis of 2-aminobenzothiazoles from a transition-metal-free reaction between aryl isothiocyanates ando-nitroaniline
in the presence of K CO is reported. The newly developed method is an efficient and cost-effective approach to synthesise
2-aminobenzothiazol2es. 3
Keywords: 2-aminobenzothiazoles, aryl isothiocyanates, o-nitroaniline, new precursor
2-Aminobenzothiazole derivatives have attracted considerable
attention due to their promising biological applications
in drug discovery and development for the treatments of
epilepsy,1 tuberculosis,2 inflammation,3 diabetes,4 viral
infection,5 tumours6 and allergies.7 Riluzole8 (A) is used to treat
amyotrophic lateral sclerosis and R116010 (B) exhibits anti-
tumour activity9 (Fig. 1).
strategies have been developed for the synthesis of these
compounds. Although the above methods for the synthesis
of 2-aminobenzothiazole derivatives have advantages, many
of these procedures have some disadvantages including low
yields, various uses of reagents, high cost catalysts, high
temperatures for completion of the reaction as well as prolonged
reaction times. On the other hand, much attention has been
paid to the use of 2-haloanilines and 2-aminothiophenols as
precursors that provide another limitation for these methods.
As part of our continuing efforts for the expeditious synthesis
of biologically relevant heterocyclic compounds27 and by
taking advantage of recent experience in the use of nitroarenes
in coupling reactions,28,29 we now report our recent efforts
towards the synthesis of diverse 2-aminobenzothiazoles via
tandem addition–cyclisation reactions of o-nitroaniline (as
a new precursor) with aryl isothiocyanates in DMSO. This
transformation proceeded smoothly under mild conditions in
the presence of K2CO3 and the corresponding products were
generated in good to excellent yields (Scheme 1).
H
N
S
NMe2
F3CO
S
N
N
NH2
N
A
B
N
Fig. 1 Chemical structures of Riluzole (A) and R116010 (B).
Historically,2-aminobenzothiazolederivativeswereprepared
by using different catalysts or agents. Hoffmann10 first reported
the formation of 2-anilinobenzothiazole from the reaction of
2-aminothiophenol and phenyl isothiocyanate. Some groups
have synthesised aminobenzothiazoles by cyclisations of
substituted anilines with the help of potassium and ammonium
thiocyanates11–15 in the presence of bromine as catalyst.
Phenylthiourea derivatives have also been employed for the
synthesis of these important compounds.16–18 Transition metal-
catalysed(PdorCu)intramolecularcyclisationof(2-halophenyl)
thioureas is a powerful strategy for construction of the
2-aminobenzothiazole core.19–21 Recently, copper(I)-catalysed
tandem addition–cyclisation reactions of 2-iodoanilines with
isothiocyanates in toluene have been described.22 A green,
alternative tandem approach based on the FeCl3-catalysed
reaction of 2-iodoaniline with isothiocyanates in water has been
reported.23 Another investigation has been carried out using
DDQ to promote C–S bond formation under transition-metal-,
ligand- and base-free conditions.24 Direct functionalisation
of aromatic C–H bonds to construct C–S bonds, provided
another access to benzothiazoles.25 A simple protocol for the
arylation process of different aromatic heterocycles including
benzotriazoles without any transition-metal catalyst, involving
the use of an excess of potassium hydroxide in dimethyl
sulfoxide, has been reported.26 Therefore, a variety of effective
Results and discussion
To optimise the reaction conditions, the in situ generated
thiourea, obtained by treating phenyl isothiocyanate 1a
(1 equiv.) with o-nitroanilinine 2 (1 equiv.), followed by the
addition of base and solvent with heating for 5 h, afforded the
product 2-aminobenzothiazole 3a, as depicted in Table 1. It
was found that the highest yields were obtained using K2CO3
(2 equiv.) as base and DMSO as solvent at 110 °C (entry 4).
Table 1 Optimisation of the reaction conditions for the preparation of 3a
Entry
Solvent
–
Base
T/oC
110
110
80
110
110
110
110
110
Yield/%a
1
2
3
4
5
6
7
8
K2CO3 (2 equiv.)
K2CO3 (1 equiv.)
K2CO3 (2 equiv.)
K2CO3 (2 equiv.)
KOH (1 equiv.)
KOH (2 equiv.)
KOH (2 equiv.)
K2CO3 (2 equiv.)
–
62
70
82
45
55
55
43
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMF
aIsolated yield
NH2
S
K2CO3 , DMSO
110oC
NH
R
R-N=C=S
+
N
NO2
1
3
2
Scheme 1
* Correspondent. E-mail: Behrooz.mirza@yahoo.com
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JOURNAL OF CHEMICAL RESEARCH 2013 779
J=8.0 Hz, 1H, p-tolyl), 7.21 (d, J=7.8 Hz, 2H, p-tolyl), 7.30 (t, J=7.8 Hz,
1H, p-tolyl), 7.32 (app. d, Japp. =8.1 Hz, 2H), 7.45 (app. d, Japp.=7.5 Hz,
1H), 7.60 (app. d, Japp.=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 19.9,
119.1, 120.8, 121.1, 121.9, 125.4, 129.3, 129.9, 134.1, 137.1, 151.2, 165.5.
Using the optimised conditions, the scope and generality of
this transformation were examined by using various phenyl
isothiocyanates and the corresponding results are listed in
Table 2.
Table 2 Synthesis of 2-aminobenzothiazoles 3
Received 14 August 2013; accepted 27 October 2013
Paper 1302131 doi: 10.3184/174751913X13848836801606
Published online: 6 December 2013
3
R
Yield/%
M.p./°C
Lit. m.p./°C
a
b
c
d
e
f
C6H5
82
80
75
82
79
80
78
80
157–159
179–180
154–155
208–209
151–153
90–94
158–16030
178–17930
153–15530
208–20930
150–15331
91–9531
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3,5-(CF3)2C6H3
t-Bu
References
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4-FC6H4
2,4-(CH3)2C6H3
213–214
134–137
216–21730
135–13632
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Conclusion
In conclusion we have developed a simple and efficient tandem
reaction for the synthesis of 2-aminobenzothiazoles from
isothiocyanates and o-nitroaniline under basic conditions in
DMSO without the presence of expensive catalysts or ligands.
Of particular importance, the requirement for an ortho-halo
and ortho-thio-substituted precursor for synthesising of
2-aminobenzothiazoles could be eliminated by this procedure.
5
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8
9
Experimental
All chemicals used in this work were purchased from Merck and
Aldrich companies. All the reactions were checked by TLC using
silica-coated plates. The products obtained by the new procedure were
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2-Anilinobenzothiazole (3a): White solid, m.p. 157–159 °C (lit.
1
158–160 °C); H NMR (500 MHz, CDCl3) δ 7.09–7.17 (m, 2H), 7.25 (t,
J=7.5 Hz, 1H), 7.40 (t, J=8.1 Hz, 2H), 7.50 (app. d, Japp. =8.0 Hz, 2H),
7.55 (app. d, Japp. =7.9 Hz, 1H), 7.60 (app. d, Japp. =7.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 118.1, 119.3, 120.4, 121.5, 123.1, 125.1, 128.8, 129.1,
138.9, 150.2, 164.
2-(4-Methylanilino)benzothiazole (3b): White solid, m.p. 179–180 °C
(lit. 178–179 °C); 1H NMR (500 MHz, CDCl3) δ 2.31 (s, 3H), 7.12 (d,
JCR1302131_FINAL.indd 779
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