Copper-II mediated tandem reaction between aromatic ketones and 2-aminobenzenethiol for the synthesis of 2-aroylbenzothiazoles

Article abstract of DOI:10.1016/j.tetlet.2016.04.058

A novel copper(II) mediated tandem reaction was developed for the synthesis of 2-aroylbenzothiazoles from readily available aryl-alkyl ketones in the presence of oxygen in ethanol. This method is mild, operationally simple, makes the use of inexpensive Cu

Full text of DOI:10.1016/j.tetlet.2016.04.058

Accepted Manuscript
Copper-II mediated tandem reaction between aromatic ketones and 2-amino-
benzenethiol for the synthesis of 2-aroylbenzothiazoles
Jaishree K. Mali, Devidas A. Mali, Vikas N. Telvekar
PII:
S0040-4039(16)30420-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.058
TETL 47558
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
4 February 2016
16 April 2016
18 April 2016
Please cite this article as: Mali, J.K., Mali, D.A., Telvekar, V.N., Copper-II mediated tandem reaction between
aromatic ketones and 2-aminobenzenethiol for the synthesis of 2-aroylbenzothiazoles, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.058
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1
Tetrahedron Letters
Copper-II mediated tandem reaction between aromatic ketones and 2-
aminobenzenethiol for the synthesis of 2-aroylbenzothiazoles
Jaishree K. Mali, Devidas A. Mali, Vikas N. Telvekar*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga,
Mumbai-400 019, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel copper (II) mediated tandem reaction was developed for the synthesis of 2-
aroylbenzothiazoles from readily available aryl-alkyl ketones in the presence of oxygen in
ethanol. This method is mild, operationally simple, makes the use of inexpensive CuBr2 as
mediator and affords the corresponding 2-aroylbenzothiazoles in moderate to good yield.
Available online
Keywords:
Acetophenone
2-Aminobenzenethiol
Cupric bromide
2-Acylbenzothiazole
Ethanol
Benzothiazole moieties have gained interest because of their
widespread applications not only in medicinal chemistry but also
in agrochemicals, industrial dyes and functional material.1
Among them 2-substituted aroyl benzothiazoles are one of the
most important class of heterocycles, with wide range of
biological activities such as antitumor, antidiabetic, and
antiviral.2 Besides this, their potential has also been explored as
fatty acid amide hydrolase inhibitor, prolyl carboxy peptidase
inhibitor,17β hydroxysteroid dehydrogenase inhibitor.2
of DMSO gets converted into phenylglyoxal or hydrated
hemiacetal. After formation of phenylglyoxal or hydrated
hemiacetal, 2-aminobenzenethiol was added and 2-
acylbenzothiazole was isolated as a final product. Similarly, 2-
hydroxy-1-phenyl ethanone and 2-hydroxy-aromatic ketones in
presence of I2/IBX in DMSO were first converted into
phenylglyoxal and then treated with 2-aminobenzenethiol to get
the final product.5b
It is also reported that, 2-acylbenzothiazole was obtained when
acetophenone, reacted with benzothiazole in DMSO, in the
presence of reagents like FeCl3.6H2O with K2S2O8;5c FeCl3.6H2O
with ligand;5d copper (I) iodide5e and iodine with KOH.5f But in
case of FeCl3.6H2O with K2S2O8 non-selective 2-acyl and 2-
arylbenzothiazoles products were obtained.
2-acylbenzothiazoles are seldom synthesized as it is difficult to
introduce acyl group at 2-position of benzothiazoles. Generally,
2-acylbenzothiazoles are synthesized by metallation of
benzothiazoles with n-butyllithium or other lithium reagents at
-78oC, followed by reaction with suitable electrophile. Overall,
these reactions require multiple step and highly reactive lithium
salts making it imperative to maintain very low temperature.2, 3
Only few methods have been reported for the synthesis of 2-
acylbenzothiazole as compared to 2-arylbenzothiazoles.4 Among
them, only one method is reported for the synthesis of 2-
acylbenzothiazole from acetophenone and 2-aminobenzenethiol,
where iodine was used to promote oxidative functionalization of
the sp3 C-H bond of 2-arylalkyl ketones in presence of DMSO as
an oxidant.5a In another method, one pot strategy was applied,
where styrene or arylacetylene in presence of I2/IBX in DMSO
was heated for 2-3 hours and after addition of 2-
All the above methods have employed DMSO as an oxidant
which played a crucial role in transforming acetophenone or
haloacetophenone into phenylglyoxal a key
intermediate
(Kornblum Oxidation) to obtain the final product 2-
acylbenzothiazole.
Although many of these methods provides efficient route to 2-
acylbenzothiazoles but they require DMSO as a oxidant, harsh
reaction condition like high reaction temperature, long reaction
times and tedious workup procedure. Thus, the development of
novel reaction system under mild reaction condition is necessary.
aminobenzenethiol, final product 2-acylbenzothiazole
was
isolated. In this, it was postulated that styrene or arylacetylene
was first converted into phenacyl iodine in presence of I2 and
IBX in DMSO, where IBX in DMSO acted as an oxidizing agent,
while I2 as an additive. Further this phenacyl iodine in presence
Transition-metal-catalyzed domino reactions have gained lot of
interest in the area of research due to their ability to shorten
reaction procedures, reduce wastes and use of mild conditions.
Amongst them copper salts are relatively inexpensive, easy to
handle, possess low toxicity and exhibit good functional
tolerance.6 Herein, we describe the novel system for synthesis of
 Corresponding author. Tel.: + 91 22 3361 2213; fax: +91 22 3361 1020
E-mail: vikastelvekar@rediffmail.com

2
Tetrahedron
2-acylbenzothiazoles and their derivatives from aryl ketones
With this optimized conditions in hand, scope of both aromatic
and hetroaromatic ketones were established and results are
presented in Table 2. It was noted that both electron donating and
withdrawing groups are suitable for this transformation to get the
corresponding product in moderate to good yield (Table 2, entries
2-7). Under this reaction condition, groups like methoxy were
stable (Table 2, entries 3-4). Hetroaromatic groups also afforded
and 2-aminobenzenethiols via copper salt mediated tandem
reaction in presence of ethanol as a solvent.
moderate to good yield (Table 2, entries 8-10). Bulkier
substituent such as naphthyl was also well tolerated under this
reaction condition (Table 2, entry 11).
Scheme 1. Synthesis of 2-acyl benzothiazoles
We initiated the present study with acetophenone and 2-
aminobenzenethiol as model substrate in the presence of different
copper salts in ethanol as a solvent at reflux temperature for 12
hours (Scheme 1) It was observed, that only Cupric bromide (1.5
equivalent) gave the desired product 2-acylbenzothiazole in 40%
yield. No reaction was observed below 1.5 equivalent of CuBr2,
while use of 2 equivalent of CuBr2 resulted into desired product
2-acylbenzothiazole in 75% yield along with traces of 2-
arylbenzothiazole as a side product. Further increase in the
amount of CuBr2 did not influence the yield. Attempt was made
to improve the yield of desired product and hence along with 1.5
equivalent of CuBr2 various co-oxidants like K2S2O8, H2O2,
TBHP, Oxone, mCPBA were examined, but no significant
change in the yield of the desired product was found. Finally, the
reaction was conducted in the presence of oxygen atmosphere
wherein 86% of the desired product was obtained without the
formation of any side product. After optimizing the reaction
conditions, it was observed that after 8 hrs under oxygen
atmosphere in presence of 1.0 equivalent of CuBr2 the desired
product was obtained in good yield without any side product.
Other copper salts under identical condition proved to be
unsuccessful (Table 1).
Table 2. Scope of aryl methyl ketones a
Entry
1
R
Productb
Yield (%)c
86
2
3
83
85
Table 1. Optimization of the reaction conditions. a
4
62
Entry
1
% Yieldb
NR
40
Copper salt
CuBr2 (1.0)
CuBr2 (1.5)
CuCl (2.0)
CuBr (2.0)
CuI (2.0)
Co-oxidant
---
2
---
3
NR
NR
NR
NR
75
---
4
---
5
---
5
6
7
82
78
62
6
Cu (OAc)2 (2.0)
CuBr2 (2.0)
CuBr2 (1.5)
CuBr2 (1.5)
CuBr2 (1.5)
---
7
---
8
40
Oxone
K2S2O8
aq. TBHP
m-CPBA
aq. H2O2
Oxygen
Oxygen
Oxygen
9
40
10
11
12
13
14
15
45
44
CuBr2 (1.5)
CuBr2 (1.5)
42
CuBr2 (1.5)
CuBr2 (1.0)
CuBr2 (0.5)
86
86
40
a
Reaction conditions: 2-aminobenzenethiol (1.2mmol), acetophenone
(1.0 mmol), in ethanol at reflux temperature for 8-12h. b Isolated yields
of 2-acyl benzothiazole after column chromatography. c NR : no reaction
8
9
75
80
Further we screened various solvents under optimized reaction
conditions and it was interesting to know that no product was
obtained in non polar solvents like toluene, 1,4-Dioxane, DCM
and CHCl3 whereas in polar aprotic solvents such as DMF,THF,
ACN a trace amount of desired product was formed. In case of
polar protic solvents such as ethanol and water, maximum yield
was obtained in ethanol as compared to water (40%) and hence
ethanol was chosen as suitable solvent for this reaction.

3
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11
78
70
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a
Reaction conditions : 2-aminobenzenethiol (1.2 mmol), aryl-alkyl
ketones (1.0 mmol), CuBr2 (1.0 mmol) in ethanol at reflux temperature
b
for 8h under Oxygen atmosphere.
Structures were confirmed by
comparison of their NMR spectra, Mass spectra and melting points with
literature data. c Isolated yields after column chromatography.
It was observed that in case of aliphatic ketones, such as methyl
ethyl ketone; isobutyl-2-methyl ketone, no desired products were
obtained. It was also observed that, substituted 2-
aminothiophenol like 2-amino-4-chlorobenzenethiol also reacted
with acetophenone to afford the desired product 5-chloro-1, 3-
benzothiazol-2-yl(phenyl)methanone in 75% yield.
A plausible reaction mechanism for the tandem reaction is
illustrated in Scheme 2. In the first step, bromination of aryl-alkyl
ketones (A) gives α-bromoketones (B).7a Later nucleophilic
substitution of amines with α-bromoketones (B) generates α-
3.
4.
(a) Wu, X. F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew.
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69, 8903
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Subsequent intramolecular
7c
nucleophilic attack by thiol leads to ring closure, generating
intermediate (E). Finally, the intermediate (E) undergoes
oxidative dehydrogenation to afford the desired product.
5.
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Scheme 2. Plausible reaction mechanism
In conclusion, we have developed simple, mild and efficient
aerobic, copper-II mediated tandem protocol for the synthesis of
2-aroylbenzothiazoles. The protocol uses inexpensive copper salt,
economic and environmentally friendly oxygen as the oxidant
along with readily available aryl alkyl ketones as a starting
material. Various functional groups were well tolerated leading to
moderate to good yield. Absence of DMSO as a solvent suggests
that the reaction follows a distinct path from Kornblum oxidation
of alpha haloketones.
6.
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8.
General Procedure for preparation of 2- aroylbenzothiazoles
A mixture of aryl-alkyl ketones (1.0 mmol), 2-aminobenzenethiol
(1.2 mmol) and CuBr2 (1.0 mmol) was stirred in ethanol. The reaction
mixture was bubbled with oxygen (balloon) and was heated to reflux
temperature for 8 hours. After completion of the reaction (monitored
by TLC), the reaction mixture was diluted with water, and then
extracted with ethyl acetate. The organic extract was washed with
Na2S2O3 solution, dried over anhydrous Na2SO4 and concentrated
under reduced pressure to get the crude product. The product was
then purified with silica gel column chromatography (Hexane-
EtOAc).
Acknowledgment
JKM and DAM thank University Grants Commission India
(UGC-SAP) for financial support. VNT thanks the Science and
Engineering Research Board (SERB), New Delhi, India, for
providing financial support.
Supplementary data
Experimental procedure and spectral data associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2016

Graphical Abstract
Copper-II mediated tandem reaction
Leave this area blank for abstract info.
between
aromatic
ketones
and
2-
aminobenzenethiol for the synthesis of 2-
aroylbenzothiazoles
Jaishree K. Mali, Devidas A. Mali, Vikas N. Telvekar*

4
Tetrahedron
Highlights




Tandem one step reaction for the synthesis of 2-aroylbenzothiazoles is developed
Inexpensive, non-toxic, readily available copper (II) bromide is used as a mediator
Absence of DMSO as a solvent, suggests that the reaction follows distinct path from Kornblum oxidation
Desired products were obtained in moderate to good yields using a simple work-up procedure