A convenient access to substituted benzothiazole scaffolds via intramolecular cyclization of thioformanilides

Article abstract of DOI:10.1016/j.tetlet.2006.11.105

A new and practical method has been developed for the synthesis of substituted benzothiazoles via the intramolecular cyclization of thioformanilides using DDQ in CH₂Cl₂ at ambient temperature. The reaction proceeds in high yields via

Full text of DOI:10.1016/j.tetlet.2006.11.105

Tetrahedron Letters 48 (2007) 669–672
A convenient access to substituted benzothiazole scaffolds
via intramolecular cyclization of thioformanilides
D. Subhas Bose* and Mohd. Idrees
Organic Chemistry Division III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Received 27 August 2006; revised 8 November 2006; accepted 16 November 2006
Available online 11 December 2006
Abstract—A new and practical method has been developed for the synthesis of substituted benzothiazoles via the intramolecular
cyclization of thioformanilides using DDQ in CH2Cl2 at ambient temperature. The reaction proceeds in high yields via the thiyl
radical to give novel oxybis-benzothiazole, and offers a high degree of flexibility with regard to the functional groups that can be
placed on the benzothiazole nucleus or 2-aryl moiety which in turn generates scaffolds for parallel synthesis.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Over the past decade the privileged structure concept
has emerged as a fruitful approach for the discovery of
novel biologically active molecules. Privileged struc-
tures, with their inherent affinity for diverse biological
receptors, represent an ideal source of core scaffolds
and capping fragments for the design and synthesis of
combinatorial libraries targeted at various receptors on
a reasonable time scale.1 Arylbenzothiazoles bearing a
substituent at C-2 are of great interest as this structural
framework has proved to be an important class of bicy-
clic privileged substructures owing to their potent utility
as imaging agents for b-amyloid, as chemiluminescent
agents, antitumour agents, calcium channel antagonists,
antituberculotics, antiparasitics and also as photosensi-
tizers.2–7
methods include microwave-mediated reaction of o-ami-
nothiophenol with b-chlorocinnamaldehydes, reaction
of dibenzyl disulfides with o-aminothiophenol, reduc-
tion of o,o0-dinitrodiphenyl disulfide, reaction of S-aryl
thiobenzoate with arylhaloamines, from 1,2,3-benzodi-
thiazole-2-oxides, via radical cyclization of benzyne
intermediates and Grignard reactions of arylisothiocya-
nates.11–16 More recently, arylbenzothiazoles have been
prepared by the oxidative coupling of thiophenols and
aromatic nitriles17 using ceric ammonium nitrate
(CAN). However, the reported synthesis of 2-arylbenzo-
thiazoles mediated by CAN is irreproducible; the only
products formed in this reaction are bis-(p-tolyl) disul-
fide and p-tolyl p-toluenethiosulfonate.18 These strate-
gies, however, were found to be incompatible with a
nitro functionality, thus requiring multistep synthesis.
Therefore, a new alternative route needs to be explored
having significant practical value for the synthesis of 2-
arylbenzothiazoles. To overcome these limitations, here-
in, we report a highly efficient intramolecular cyclization
of thioformanilides mediated by 2,3-dichloro-5,6-di-
cyanobenzoquinone (DDQ)19 without using any metal
catalyst. DDQ is a well-known oxidizing agent and
has proved to be a versatile reagent for various organic
transformations including deprotection of functional
groups, cleavage of linker molecules from solid sup-
ports, introduction of unsaturation and potential appli-
cations for the construction of carbon–carbon and
carbon–heteroatom bonds.
Arylbenzothiazoles are most commonly synthesized via
one of two major routes. The most commonly used
method involves the condensation of o-aminothiophe-
nols with substituted nitriles, aldehydes, carboxylic
acids, acyl chlorides or esters.8 This method, however,
suffers from limitations such as difficulties encountered
in the synthesis of readily oxidizable o-aminothiophe-
nols bearing substituents. Another route is based on Jac-
obson’s cyclization of thiobenzanilides.9,10 Other general
Keywords: Cyclization; Thioformanilide; Thiyl radical; DDQ;
Benzothiazole.
*
Corresponding author at present address: Korea Research Institute
of Chemical Technology, PO Box 107, Yuseong, Daejeon 305-600,
South Korea. Fax: +91 40 27160387; e-mail addresses:
dsb@iict.res.in; bose_iict@yahoo.co.in
In continuation of our efforts towards the synthesis
and development of new methodologies in organic
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.105

670
D. S. Bose, M. Idrees / Tetrahedron Letters 48 (2007) 669–672
H3CO
S
H3CO
DDQ, CH2Cl2
RT, 20 min
S
N
NO2
N
H
NO2
1
2
Scheme 1. DDQ-mediated intramolecular cyclization of thioformanilide.
synthesis,20 we herein describe a new, efficient and prac-
tical route for the one-step conversion of thioformani-
lides into the corresponding benzothiazoles using
DDQ in CH2Cl2 at room temperature in excellent yields
(Scheme 1).21 To the best of our knowledge, the general-
ity and applicability of DDQ in the preparation of ben-
zothiazoles from thioformanilides is not known. In
addition, this reaction is very clean, efficient and
Table 1. DDQ-catalyzed synthesis of 2-arylbenzothiazoles
Entry
Product
Yielda (%)
95
O
H3CO
S
N
S
N
1
O
2a
2b
H3CO
2
3
4
5
879a
NO2
OCH3
H3CO
H3CO
S
N
92
2c
H3C
NO2
O
S
N
88
O
2d
F
S
N
NO2
85
2e
CH3
F
HO
S
N
NO2
CH3
6
7
83
90
2f
H3CO
S
N
CH3
2g
S
N
8
9
95
2h
O
O
S
S
H3C
CH3
85
89
N
N
2i
S
N
2j
10
CH3
a Yield refers to the pure isolated product.

D. S. Bose, M. Idrees / Tetrahedron Letters 48 (2007) 669–672
671
H3CO
H3CO
H3CO
.
S
S
SH
DDQ
N
H
N
N
1b
1
1a
NO2
NO2
NO2
NO2
H3CO
H3CO
S
N
S
N
.
NO2
2
1c
Scheme 2. A plausible mechanism for the DDQ-mediated intramolecular cyclization of thioformanilides.
involves a simple work-up procedure. Unlike previous
methods, the reported protocol does not require high
temperatures to produce benzothiazole derivatives. Sol-
vents such as CH3CN, THF, MeOH and the ionic liquid
[BMIM]PF6 proved to be effective. It should be noted that
other reagents such as iodotrimethylsilane and molecular
iodine were ineffective even after longer reaction times,
demonstrating the unique ability of DDQ in this cycliza-
tion. The most versatile route to 2-arylbenzothiazoles
bearing substituents on both the phenyl and benzothiaz-
olyl rings started with benzanilides prepared by the reac-
tion of benzoyl chlorides and arylamines in triethylamine.
The benzanilides were converted to thiobenzanilides with
Lawesson’s reagent22 in refluxing dry toluene.
2-substituted benzothiazoles in high yields with a com-
plete selectivity. Further investigations for broadening
the synthetic application of this cyclization to develop
a combinatorial version for the SAR studies of 2-aryl-
benzothiazoles for various pharmaceutical applications
are currently in progress.
Acknowledgement
One of the authors (M.I.) thanks CSIR, New Delhi, for
financial support.
To explore the generality and scope of this process, di-
verse thioformanilides were studied for the synthesis of
arylbenzothiazoles and the results are summarized in
Table 1. As shown in Table 1, the synthesis of 2-aryl-
benzothiazoles bearing substituents on both rings was
accomplished in high yields. It can be further seen that
2-arylbenzothiazoles bearing a nitro functionality on
the aryl ring (entries 2, 3, 5 and 6) were obtained in
quantitative yields by this method. This contrasts, with
the Bu3SnH/AIBN-promoted23 cyclization of aryl radi-
cals onto thioamides for the synthesis of arylbenzothiaz-
oles, where, under these conditions thioamides
containing a nitro functionality on the aryl ring under-
went decomposition rather than benzothiazole forma-
tion. Furthermore, we have synthesized for the first
time, a bis(benzothiazole) possessing an oxygen bridge
between the rings. Since a wide variety of aryl amines
and acids are commercially available, this protocol of-
fers a high degree of flexibility with regard to functional
groups on the benzothiazole nucleus or 2-aryl moiety,
thereby providing a means for understanding struc-
ture–activity relationships (SAR) of the target com-
pounds. The method is compatible with many
substituents such as alkoxy, nitro and tert-butyl.
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672
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at room temperature. The progress of the reaction was
monitored by TLC. After completion, the reaction was
quenched with H2O (2 · 5 ml) and the reaction mixture
was extracted with CH2Cl2 (2 · 10 ml). The combined
organic phase was dried with anhydrous Na2SO4 and the
solvent was removed in vacuo, to afford the crude product
which was purified by column chromatography on silica
gel using petroleum ether/EtOAc, 8:1 as the eluent to give
2-arylbenzothiazoles 2a–j in 83–95% yields. Compound
2a: Pale yellow solid. Yield. 95%. Mp 164–166 ꢁC, 1H
NMR (CDCl3) d 3.88 (s, 3H), 6.02 (s, 2H), 6.83 (d, 1H,
J = 8.3 Hz), 7.02 (dd, J = 2.26, 6.8 Hz, 1H), 7.25 (1H, d,
J = 3.0 Hz), 7.48–7.58 (m, 2H), 7.85 (d, 1H, J = 9.0 Hz).
13C NMR (75 MHz): d 55.8, 101.6, 104.4, 107.3, 108.6,
115.4, 122.0, 123.5, 128.3, 136.3, 148.4, 148.7, 149.8, 157.7.
HRMS (ESI): m/z calcd for C15H11NO3S: 286.0537;
found: 286.0537. Compound 2i: Light yellow solid. Yield:
1
85%. Mp 216–217 ꢁC; H NMR (CDCl3) d 2.48 (s, 6H),
7.18–7.28 (m, 6H), 7.51 (s, 2H), 7.89–8.02 (m, 6H). 13C
NMR (75 MHz): d 21.5, 111.0, 118.7, 124.0, 127.3, 129.7,
130.9, 136.3, 141.4, 150.3, 155.3. HRMS (ESI): m/z calcd
for C28H21N2OS2 (M+H): 465.1095; found: 465.1100.
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