Concise Access to 2-Aroylbenzothiazoles by Redox Condensation Reaction between o-Halonitrobenzenes, Acetophenones, and Elemental Sulfur

Article abstract of DOI:10.1021/acs.orglett.5b01182

A wide range of 2-aroylbenzothiazoles 3 including some pharmacologically relevant derivatives can be obtained in high yields by simply heating o-halonitrobenzenes 1, acetophenones 2, elemental sulfur, and N-methylmorpholine. This three-component nitro methyl coupling was found to occur in an excellent atom-, step-, and redox-efficient manner in which elemental sulfur played the role of nucleophile building block and redox moderating agent to fulfill electronic requirements of the global reaction. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01182

Letter
pubs.acs.org/OrgLett
Concise Access to 2‑Aroylbenzothiazoles by Redox Condensation
Reaction between o‑Halonitrobenzenes, Acetophenones, and
Elemental Sulfur
Thanh Binh Nguyen,* Karine Pasturaud, Ludmila Ermolenko, and Ali Al-Mourabit*
Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR 2301, Universite
91198 Cedex, France
́
Paris-Sud, 1 avenue de la Terrase, Gif-sur-Yvette
S
* Supporting Information
ABSTRACT: A wide range of 2-aroylbenzothiazoles 3
including some pharmacologically relevant derivatives can be
obtained in high yields by simply heating o-halonitrobenzenes
1, acetophenones 2, elemental sulfur, and N-methylmorpho-
line. This three-component nitro methyl coupling was found
to occur in an excellent atom-, step-, and redox-efficient
manner in which elemental sulfur played the role of
nucleophile building block and redox moderating agent to
fulfill electronic requirements of the global reaction.
closely related derivatives of 2-aroylbenzothiazoles were also
identified as useful molecules in medicinal chemistry; for
example, AC-265347 (9) was reported to be a calcium-sensing
receptor agonist6 and lidorestat (10) an aldose reductase
inhibitor (for treatments for chronic diabetic complications).7
The synthesis of these derivatives relies on transformations
from anilines (o-aminothiophenols8 or dimers,9 o-iodoani-
lines10) or preformed benzothiazoles (2-unsubstituted,11 2-
benzyl,9,12 2-(α-hydroxybenzyl)benzothiazoles1). Although
these methods can offer a wide range of structures, they suffer
from some intrinsic drawbacks of low atom-, step-, and redox-
efficiency. First, aniline and benzothiazole starting materials are
not always readily available, and additional steps of preparation of
starting material are generally required. Moreover, in the case of
anilines,8,10 reduced derivatives of phenyl glyoxylic acetophe-
nones, phenylacetylenes, phenylglyoxals, etc., have been used as
coupling partners. The global transformation required an
external oxidizing agent. It should be noted that o-halonitro-
benzenes are inexpensive, readily available, and stable starting
materials for both anilines and benzothiazoles.
2-Aroylbenzothiazoles are an important class of benzothiazole
heterocycles with various pharmaceutical applications. They exist
in a wide range of biologically active molecules such as 4 as
antiviral agents,1 5 as fatty acid amide hydrolase inhibitors,2 6 as
effective inhibitors of the antiapoptotic Bcl-2 protein which
inhibits cell growth and induces apoptosis in human breast and
prostate cancer cell lines,3 and 7 as potent Ca2+/calmodulin-
dependent protein kinase II (CaMKII) inhibitors (Figure 1).4
Moreover, 8 showed a promising profile regarding activity in
T47-D cells, selectivity toward ERα and ERβ, inhibition of
hepatic CYP enzymes, metabolic stability, and inhibition of
marmoset 17β-HSD1 and 17β-HSD2.5 Additionally, some
We have previously shown that access to 2-hetarylbenzothia-
zoles could be achieved using a three-component nitro-methyl
redox condensation between o-halonitrobenzene, 2-methylhe-
tarene, and elemental sulfur.13 Compared to traditional
approaches based on non-redox or only oxidizing reactions,
this method emerged as an appealing alternative approach from
both environmental and economical perspectives with respect to
atom-, step-, and redox-economical requirements. In addition,
the starting materials for this method are inexpensive and readily
available in great structural diversity.
Received: April 22, 2015
Figure 1. Bioactive 2-aroylbenzothiazoles and derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01182
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Organic Letters
Letter
Continuing our efforts on the straightforward access to this
heterocycle through three-component nitro-methyl redox
condensation, we attempted to use acetophenones as reducing
coupling partners (Scheme 1). The objective was also to have
methylmorpholine and N-methylpiperidine gave better yields
than heteroaromatic bases such as 3-picoline and pyridine, even
at lower temperature. The best yield (86%) was achieved with N-
methylmorpholine at 120 °C (entry 5). Lower molar ratios of
either acetophenone or sulfur resulted in lower yields (results not
shown). We were pleased to find that the reaction was general for
other o-halogen substituents with only slight differences in
reactivity.
Scheme 1. Access to 2-Aroylbenzothiazoles
Having established the optimized the reaction conditions, we
studied the scope of the reaction by examining first a series of 2-
halonitrobenzenes 1 and acetophenone 2a. As presented in
Figure 2, under the optimized conditions, a wide range of
Figure 2. Scope of o-chloronitrobenzenes 1a with acetophenone 2a.
available an efficient and flexible method for the preparation of
analogs of compounds 4−10. Readily available in a wide range of
structures (from acetylation reactions of aromatic compounds,
for example), these substrates could furnish six electrons
required by the nitro groups, thus avoiding redox redundant
transformations and providing a very direct approach to 2-
aroylbenzothiazoles.
The use of an additional base can be intuitively envisioned as
the result of a removal of one hydrogen chloride molecule. An
optimization study focusing on the choice of base and the
reaction stoichiometry has been carried out between o-
chloronitrobenzene 1a, sulfur, and acetophenone 2a (Table 1).
Indeed, no product 3aa was detected in the absence of a base
(entry 1). Small nitrogen bases such as pyridine, 3-picoline, N-
methylpiperidine, and N-methylmorpholine were chosen on the
basis of their stability to the oxidation reaction with elemental
sulfur and the aromatic nucleophilic substitution reaction with o-
chloronitrobenzene (entries 2−5). Alicyclic bases as N-
functional groups in 1 could tolerate the reaction conditions. To
our delight, the reaction conditions could be applied to variety of
useful functional groups on both organic components, including
methyl, fluoro, chloro, bromo, methoxy, and trifluoromethyl
substituents (products 3ba−ga). The o-chloronitro compound
derived from pyridine was also a suitable substrate for this redox
condensation, furnishing the desired product in moderate yield
(3ia). Pleasingly, 2,3,4-trichloronitrobenzene was highly com-
patible with the reaction conditions and was efficiently converted
into the corresponding dichloro product 3ja in good yield. It
should be noted that o- and p-chloro groups are both strongly
activated by the nitro group, but the sulfuration occurred
exclusively with the o-chloro substituent.
Subsequently, we turned our attention to the use of various
methyl ketones 2b−n as reducing coupling partners with 1a
(Scheme 2). Satisfactory yields were obtained when methyl,
methoxy, phenoxy, acetamido, or chloro substituents were
present in the acetophenone scaffold (3ab−ai).
Table 1. Screening of Reaction Conditions
Notably, reaction of 2′,4′-dimethylacetophenone and 2′,4′,6′-
trimethylacetophenone required a higher temperature to give a
yield comparable to that of other substrates (3ah), which might
be attributed to steric hindrance effects of the o-methyl groups.
Interestingly, benzothiazolyl ketones with polyaromatic or
heteroaromatic substituents, such as 2-naphthyl, 2-thienyl,
pyridyl, furyl, and indolyl groups (3aj−an), could also be
obtained from the corresponding hetaryl methyl ketones. The
yields were higher for 2-thiophene-yl 3al than for its oxygenated
analogue 3am, which could be explained by the higher stability of
the thiophene ring. The reaction with sparingly soluble and
readily oxidizable 3-indolyl methyl ketone required a higher
temperature and DMF solvent to give a satisfactory yield of the
desired product 3an (41%).
a
b
entry
X
base
T (°C)
yield (%)
c
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
F
120
120
150
120
120
120
120
120
0
c
pyridine
<5
3-picoline
51
72
85
82
86
81
N-methylpiperidine
N-methylmorpholine
N-methylmorpholine
N-methylmorpholine
N-methylmorpholine
Br
I
For practical reasons, the use of less expensive o-chloro
derivatives was preferred for most of the above examples. On the
contrary, an attractive alternative of this reaction is the possibility
of performing it with other o-halogen derivatives. For instance,
2,5-difluoronitrobenzene and 2-chloro-5-fluoronitrobenzenes
a
Reaction condtitions: 1a (2.5 mmol), 2a (5 mmol), S (10 mmol, 320
mg), base (5 mmol). Isolated yield. Conversion determined by H
b
c
1
NMR.
B
DOI: 10.1021/acs.orglett.5b01182
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Organic Letters
Letter
of 4′-methylacetophenone 2b and the desired condensed
product 3ab (see the Supporting Information).
Scheme 2. Scope of Aryl Methyl Ketones 2 with o-
Chloronitrobenzene 1a
This observation suggested that only one molecule of
acetophenone was required and sulfur should play a dual role
as the redox-moderating agent by compensating for the electron
gap of the global process.
Next, starting materials were heated with N-methylmorpho-
1
line at 120 °C for 16 h. The H NMR analyses of the crude
mixtures showed that all of the organic molecules remained
unchanged except that a trace amount of 2,2′-dinitrodiphenyl
disulfide was formed when o-chloronitrobenzene, sulfur, and N-
methylmorpholine were heated together (Scheme 5). This result
indicated that the transformation involved a cascade pathway via
highly reactive intermediates.
Scheme 5. Control Experiment without Acetophenone
On the basis of these observations as well as related reactions,
we propose the mechanism shown in Scheme 6.
both provided the same condensed products in comparable
yields, but the difluoro derivative is less expensive (Scheme 3).14
Scheme 6. Proposed Mechanism
Scheme 3. Formation of 3ca Using Different o-
Halonitrobenzenes 1
Interestingly, it should be noted that benzothiazoles 3aa and
3da have been reported to have potent antiviral activity,1 whereas
molecules 3ae, 3ag, and 3ah could serve as precusors for the
construction of a fatty acid amide hydrolase inhibitor 5, CaMKII
inhibitor 7, and calcium-sensing receptor agonist AC-265347
(9), respectively.
Although the mechanism is far from well understood, some
control experiments were performed to gain further insights into
the nature of this transformation. First, the reaction stoichiom-
etry was investigated for organic components. The reaction
between o-chloronitrobenzene 1a (1 equiv) and 4′-methylace-
tophenone 2b (2 equiv) performed in a sealed tube was chosen
for this purpose (Scheme 4). Under standard conditions, the
reaction proceeded smoothly without any formation of gaseous
The process could be initiated by the reaction of sulfur with N-
methylmorpholine to reversibly generate ammonium polysulfide
zwitterion A. Subsequent nucleophilic aromatic substitution of
zwitterion A on 1a would lead to B. Thanks to the electron-
withdrawing effect of the aromatic nitro group, the S−S bond
next to the aromatic ring of B is fragile, and B would be capable of
attacking acetophenone 216 to provide sulfide C and a
homologue of zwitterion A. Activated by both a benzoyl group
and aryl sulfide group, the methylene group of sulfide C could
condense readily with the aromatic nitro group leading to nitrone
D. Reduction of D with A or homologues would provide 3 along
with double-zwitterion E. Hydrolysis of E by water (byproduct of
the steps C → D and D → E) would regenerate partially
elemental sulfur16 and lead to oxygenated sulfur compounds
(“SO”) and N-methylmorpholinium hydrochloride. Obviously, it
should be pointed out that the presence of morpholinium
1
byproducts. H NMR analysis of the crude mixture based on
methyl signals of the p-tolyl ring15 showed a clean 45:55 mixture
Scheme 4. Control Experiment with 1a and 2b
C
DOI: 10.1021/acs.orglett.5b01182
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Organic Letters
Letter
Chen, H.; Deng, G. Tetrahedron Lett. 2013, 54, 3838. (e) Gao, Q.; Wu,
X.; Jia, F.; Liu, M.; Zhu, Y.; Cai, Q.; Wu, A. J. Org. Chem. 2013, 78, 2792.
(f) Wang, J.; Zhang, X.; Chen, S.; Yu, X. Tetrahedron 2014, 70, 245.
(g) Feng, Q.; Song, Q. Adv. Synth. Catal. 2014, 356, 2445. (h) Park, S.;
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(12) Dos Santos, A.; El Kaim, L.; Grimaud, L. Org. Biomol. Chem. 2013,
11, 3282.
(13) (a) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2013,
15, 4218. For related works, see: (b) Nguyen, T. B.; Ermolenko, L.;
Retailleau, P.; Al-Mourabit, A. Angew. Chem., Int. Ed. 2014, 53, 13808.
(c) Tong, Y.; Pan, Q.; Jiang, Z.; Miao, D.; Shi, X.; Han, S. Tetrahedron
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hydrochloride could accelerate the tautomerization of acetophe-
none, thus facilitating the D → E step.
In summary, we have developed a three-component redox
condensation of a variety of o-nitrohalobenzenes and acetophe-
none with elemental sulfur, enabling a direct, inexpensive, and
easy synthesis of 2-benzoylbenzothiazoles. The choice of base is
of vital importance to the success of the transformation, and N-
methylmorpholine was found to be particularly suitable for this
role. Elemental sulfur was found to play dual roles as nucleophilic
building block and redox moderating agent to fulfill electronic
requirement of the global process. The process involves the
formation of three new bonds (two C−S and one CN) in a
highly efficient and atom-, step-, and redox-economical manner
without addition of oxidizing or reducing agents or coupling
catalyst.
(14) At the time of manuscript preparation, 2-chloro-5-fluoronitro-
benzene and 2,5-difluoronitrobenzene were commercially available
from Sigma-Aldrich for $87.40/25 g (196622-5G) and $56.70/25 g
(368709-5G), respectively.
1
(15) Only three H NMR singlet signals which correspond to one
ASSOCIATED CONTENT
* Supporting Information
■
methyl signal of the product 3ab and two methyl signals of the starting
ketone 2b were observed between 2.0 and 2.8 ppm. If other products
derived from 2b were formed, other singlet signals should be observed in
this zone.
(16) For the single example of related bis(DABCO)disulfide
dichloride salt, see: (a) Konstantinova, L. S.; Rakitin, O. A.; Rees, C.
W.; Amelichev, S. A. Mendeleev Commun. 2004, 14, 9. (b) Konstantinova,
L. S.; Amelichev, S. A.; Rakitin, O. A. Russ. Chem. Bull. 2006, 55, 2081.
(c) Konstantinova, L. S.; Lysov, K. A.; Souvorova, L. I.; Rakitin, O. A.
Beilstein J. Org. Chem. 2013, 9, 577. This compound was found to be
unstable and readily hydrolyzed to yield elemental sulfur, DABCO
hydrochloride, and other sulfur compounds with positive oxidation
states of sulfur.
S
Experimental procedure, characterization data, and NMR
spectra. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01182.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nguyen@icsn.cnrs-gif.fr.
*E-mail: ali.almourabit@icsn.cnrs-gif.fr.
Notes
The authors declare no competing financial interest.
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