Catalyst-free facile synthesis of 2-substituted benzothiazoles

Article abstract of DOI:10.1039/c3gc41255e

2-Substituted benzothiazoles were synthesized in excellent yields by a benzotriazole methodology, with the conditions being efficient, green, economical, and suitable for broad applications in medicinal chemistry and the synthesis of specialty chemicals.

Full text of DOI:10.1039/c3gc41255e

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DOI: 10.1039/C3GC41255E
A table of contents entry
Catalyst-Free Facile Synthesis of 2-Substituted Benzothiazoles
Siva S. Panda,a Mohamed A. Ibrahim,a,b Alexander A. Oliferenko,a Abdullah M. Asiric,d and Alan R.
Katritzky*a,c
A protocol for the synthesis of 2-aryl/peptidyl benzothiazoles is reported from aryl and peptidyl
benzotriazolides and 2-aminothiophenol in high yields in a one-pot reaction with in water under
microwave irradiation.

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Cite this: DOI: 10.1039/c0xx00000x
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Communication
Catalyst-Free Facile Synthesis of 2-Substituted Benzothiazoles
Siva S. Panda,a Mohamed A. Ibrahim,a,b Alexander A. Oliferenko,a Abdullah M. Asiric,d and Alan R.
Katritzky*a,c
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
(ii)
a one-pot synthesis of benzothiazoles with sodium
2-Substituted benzothiazoles are synthesized in excellent
yields by using a benzotriazole methodology, with conditions
being efficient, green, economical, and suitable for broad
applications in medicinal chemistry and synthesis of specialty
hydrosulfide as the source of sulfur.28 These methods however
use expensive catalysts (Pd) and reagents (aryl iodide) and
50 require long reaction times and high temperatures.
Benzotriazole chemistry has been practiced extensively in our
group and has often been found to be superior to conventional
routes29. In this communication we report a novel synthetic
route to 2-substituted benzothiazoles through N-acylated
55 benzotriazoles using no catalyst, auxiliary reagent or solvent.
The reaction gives quantitative yields and runs smoothly
either under microwave or conventional heating. The best
results are achieved when water is used as a reaction medium
with microwave irradiation as a source of heat. To the best of
60 our knowledge, this is the first catalyst- and auxiliary-free and
10 chemicals.
Introduction
2-Substituted azoles such as benzoxazoles, benzimidazoles,
benzothiazoles have attracted much attention because of their
importance as pharmaceuticals, bioactive compounds, and
15 imaging agents. Benzothiazoles in particular have been
studied intensively because of their antitumor,1 anti-
inflammatory,2
antimicrobial,3
antitrypanosomal,4
anticonvulsant,5 and antituberculosis activity.6 Benzothiazole
moieties are also found in fluorescent pH indicators,7 an
20 iminocoumarin-based zinc sensor,8 bioluminogenic substrate,9
environmentally
benign
synthesis
of
2-substituted
benzothiazoles affording near quantitative yields under mild
reaction conditions.
1]
cleavage agents for soluble oligomers of amyloid β-peptides
and ligands for catalytic reactions.11
Results and discussion
Because of this importance, many synthetic methods have
been developed, based on (a) condensation of 2-
25 aminothiophenol with carbonyl compounds such as
aldehydes,12–14 carboxylic acids,15–17 acid chlorides,18 or
esters;19 (b) conversion of 2-halo amides into the
corresponding thioamides using P4S10, or Lawesson’s reagent,
but generally not feasible for substrates containing ketone,
65 2-Aminothiophenol 1 and benzoyl benzotriazolide 2a couple
in quantitative yield without any catalyst or solvent if a
substantial excess (10 equiv.) of 2-aminothiophenol is used. In
fact, the reaction occurs in liquid 2-aminothiophenol, which
serves both as
a solvent and a reagent for the solid
70 benzotriazolide. Optimization of reaction conditions (Table 1)
revealed best results under microwave heating at 70 oC for 1
h; conventional heating was less efficient.
30 ester,
and
amide
moieties;20 (c) cyclization of
thioformanilides with the aid of transition-metal catalysts,21
under SNAr,22 or radical conditions,23 and cyclization of an
arylthioamide using potassium ferricyanide (Jacobson’s
method).24 Copper catalysis of reactions between iodo amides
35 and sodium sulfide25 or iodo amines and aldehydes26 have
been reported by Ma et al. and Deng et al. respectively, both
synthetic methods affording respectable yields of 2-
substituted benzothiazole.
Although, excess of one reagent is not desirable,
stoichiometric amounts of 1 and 2a–e do not afford a good
75 reaction medium, because solid benzotriazoles 2a–e
dominates on a volume-by-volume basis. We therefore ran the
reactions of 2-aminothiophenol and benzotriazoles 2a–e in
water under microwave irradiation, as shown in Scheme 1.
Excellent yields were obtained for all five aryl derivatives of
80 N-acyl benzotriazole, with melting points of the 2-
arylbenzothiazoles 3a–e being in a good agreement with the
literature (see Table 2). Equimolar reactions in water gave
yields comparable to those carried out with an excess of 2-
aminothiophenol, but the mechanism is different: since neither
85 reagents nor products are soluble in water; the reaction is
heterogeneous, and therefore controlled by diffusion. Hexane
was also tested as a reaction medium in which both reagents
are insoluble; giving almost equally good results, but non-
[journal], [year], [vol], 00–00 | 1
These methods still suffer from disadvantages such as harsh
40 reaction conditions, use of metal catalysts and additional
reagents, use of air sensitive and toxic substances,
cumbersome work-up procedures and the generation of acidic
and metallic wastes.
Recent efforts to overcome these drawbacks have included (i)
45 use of a palladium catalyzed thiol cross-coupling reaction of
2-haloanilides and 2-ethylhexyl 3-mercapto propionate27 and
This journal is © The Royal Society of Chemistry [year]

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DOI: 10.1039/C3GC41255E
Page 3 of 5
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flammable water is preferred.
Table 1 Optimization of reaction condition
Entry
Reaction temp. (oC)
20 (Room temp.)
50 (Conv.)
Reaction time
Yield (%)a
1
2
3
4
5
12 h
6 h
3 h
3 h
1 h
0
58
82
80
95
100 (Conv.)
50 (MW)
70 (MW)
aIsolated yield
30
Scheme 2 Synthesis of 2-peptidyl benzothiazole 5a–o
To elucidate the mechanism and range of applicability, 5f
(Cbz-Ala-Bt) was selected for coupling with 2-
35 aminothiophenol in five organic solvents, tap and distilled
water, and also under solvent-free conditions. The yields and
purity are shown in Table S4. Tap and distilled water gave
essentially identical results, and hexane performed almost as
well, whereas the other solvents gave inferior results to water
40 and hexane. A solvent-free reaction in an excess of 2-
aminothiophenol also gave very high yield and purity. This
somewhat surprising reactivity can be rationalized if one takes
into account the solubility characteristics of the reagents and
products. Water and hexane do not dissolve 2-
45 aminothiophenol, Cbz-Ala-Bt, or the resultant benzothiazole.
Toluene is a solvent for 2-aminothiophenol and the product
but not for Cbz-Ala-Bt, while EtOH, THF, and DMF freely
dissolve both the reagents and products. In the latter reaction
media, the reactions are homogenous and kinetically
50 controlled, as the N-acylation of 2-aminothiophenol occurs
quickly and irreversibly. The next step, cyclo condensation
needs more heating to generate the thermodynamic product,
but, as the product is soluble, it exists in equilibrium with the
reagents and therefore is produced in smaller yields with
55 similar reaction times. By contrast, the reactions in water and
hexane are more likely to be diffusion controlled, because the
reagents are sparingly soluble, and the products are virtually
insoluble in these solvents. The first step (N-acylation) occurs
quickly even at low concentrations of the reagents, while the
60 second step (cyclization) is a unimolecular reaction whose
products precipitate and thus drive the reaction to completion.
When solubilization was induced by adding 5 mol % of a
phase-transfer catalyst (Aliquat 336), the yields were
expectedly smaller thus confirming the proposed reaction
65 mechanism. The physical conditions are also important: the
uniformly penetrating microwave irradiation plus vigorous
stirring greatly improve the heat and mass transfer, which
results in significantly higher yields and purity.
5
Scheme 1 Synthesis of 2-substituted benzothiazole 3a–e
Table 2 Preparation of 2-arylbenzothiazole 3a–e
Entry
R
C6H5
4-CH3-C6H4
4-OCH3-C6H4
2-thiophenyl
1-napthyl
Yield (%)
Mp (oC)
99–100
88–89
115–116
91–93
oil
Lit. Mp (oC)
97–9927
86–8827
114–11627
92–9427
oil13
1
2
3
4
5
95
92
90
95
91
For comparison, 2-phenyl benzothiazole was synthesized
10 by the reaction of 2-aminothiophenol with benzoyl chloride,
used in 1:1 stoichiometric amounts. The reactions were run
solvent-free under both microwave and normal heating
conditions: 70 oC for 1 h. The first reaction step (amine
acylation) occurred quickly and almost violently, but the
15 second step (cyclo condensation) required either MW or
conventional heating. The yield of 2-phenylbenzothiazole was
89% under microwave and 85% under conventional heating,
but the product from the latter contained the N-acylated
intermediate. Thus benzotriazole is preferred, since it is a
20 mild and easy to control acylating agent. The benzotriazole
route is also greener, since BtH can be easily recycled.
Benzothiazoles with peptidic functions at position 2 afford
promising therapeutic or bioimaging agents with good
bioavailability. Thus we extended this “suspension-in-water”
25 methodology to the synthesis of 2-peptidylbenzothiazoles 5a–
o
by
coupling
2-aminothiophenol
with
peptidylbenzotriazolides 4a–o (Scheme 2 and Table 3). Good
to excellent yields were obtained under 50 W microwave
o
heating at 70 C in water for 1 h.
2
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DOI: 10.1039/C3GC41P25a5gEe 4 of 5
Table 3 Preparation of 2-peptidyl benzothiazole 5a–o
Entry
1
Product 5
Yield (%)
84
mp (oC)
16
88
163–165
68–70
Conclusions
2
3
82
83
70–72
In conclusion, we report a novel, facile and green conditions
for synthesis of 2-substituted benzothiazoles without the use
of catalysts, synthetic auxiliaries, or even solvent. The
heterogeneous reaction run in water produces, without loss of
chirality, almost quantitative yields of 2-aryl benzothiazoles
and 2-peptidyl benzothiazoles, promising candidates for
therapeutic or bioimaging agents. The reaction conditions
5
99–101
4
80
130–132
10 were optimized at 70 C in for one hour under microwave
irradiation. The uniform heating by MW plus vigorous stirring
improve the heat and mass transfer of the diffusion controlled
reaction thus explaining the observed high yields and
providing a plausible mechanism for the reaction. Given the
15 high yield, “greenness”, and possibility of scaling-up the
reaction has a considerable potential for adoption by the
pharma and fine chemicals industries.
5
6
7
82
78
73
123–125
92–94
88–90
Experimental Section
In a typical procedure, a mixture of 2-aminothiophenol (0.1 g,
20 0.085
mL,
0.80
mmol)
and
N-protected
8
9
78
70
220–222
180–182
aminoacylbenzotriazole or N-protected peptidylbenzotriazole
(0.80 mmol) was subjected to microwave irradiation (50 W,
70 oC) in water (3 mL) for 1 h. After completion of the
reaction, aqueous NaCO3 solution was added and the mixture
25 was extracted with ethyl acetate followed by washing with 4
N HCl. When the supernatant water retained the product in a
colloidal form, the product was isolated by extraction with
ethyl acetate. The organic phase was dried over MgSO4 and
then evaporated to obtain the desired product. Benzotriazole
30 could be recovered from the aqueous layer by pH controlled
acidification.
10
11
12
88
76
78
oil
149–151
117–116
Acknowledgements
We thank the University of Florida and the Kenan Foundation
35 for financial support. This paper was also funded in part by
generous support from King Abdulaziz University, under
grant No. (D-006/431). The authors, therefore, acknowledge
the technical and financial support of KAU. We also thank to
Dr. C. D. Hall for helpful suggestions.
13
14
15
70
89
75
179–181
184–186
110–112
40 Notes and references
aCenter for Heterocyclic Compounds, Department of Chemistry,
University of Florida, Gainesville, FL 32611-7200
Fax: 352-392-9199; Tel: 352-392-0554; E-mail: katritzky@chem.ufl.edu
bDepartment of Organic Chemistry, College of Pharmacy, Misr
45 University for Science and Technology, Al-Motamayez District, P.O. Box:
77, Egypt
cChemistry Department, King Abdulaziz University, Jeddah, 21589, Saudi
Arabia
dCenter of Excellence for Advance Materials Research (CEAMR), King
50 Abdulaziz University, Jeddah, 21589, Saudi Arabia
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