Novel synthesis of 2-arylbenzothiazoles mediated by ceric ammonium nitrate (CAN).

Article abstract of DOI:10.1021/ol020027i

[reaction: see text] Cyclization of the intermediate radical formed after initial oxidative coupling between thiophenols and aromatic nitriles leads to the synthesis of a wide range of 2-arylbenzothiazoles.

Full text of DOI:10.1021/ol020027i

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1641-1642
Novel Synthesis of 2-Arylbenzothiazoles
Mediated by Ceric Ammonium Nitrate
(CAN)
R. H. Tale*
School of Chemical Sciences, Swami Ramanand Teerth Marathwada UniVersity,
Vishnupuri, Nanded-431606, Maharashtra, India
rhtale1@rediffmail.com
Received January 25, 2002
ABSTRACT
Cyclization of the intermediate radical formed after initial oxidative coupling between thiophenols and aromatic nitriles leads to the synthesis
of a wide range of 2-arylbenzothiazoles.
The benzothiazole nucleus is of particular interest especially
within the realm of medicinal chemistry. Many useful
therapeutic agents contain the benzothiazole moiety. For
example, 2-(4-aminophenyl)benzothiazoles (I) represent a
novel class of potent and selective antitumor agents.1
Roe and Tucker reported the synthesis of 2-arylbenzothia-
zoles through the use of a bromo substituent ortho to the
anilido nitrogen and formation of a benzyne intermediate
followed by intramolecular cyclization.4 A similar strategy,
for the synthesis of a range of 7-substituted benzothiazoles
via directed metalation followed by benzyne formation and
subsequent cyclization, has also been reported.5 These
strategies, however, were found to be incompatible with nitro
functionality on the aryl ring and do not represent a general
route to 2-arylbenzothiazoles. On the basis of the strategy
of Spitulnik6 for the synthesis of 2-methylbenzothiazoles,
recently the regiospecific synthesis of 5- and 7-monosub-
stituted and 5,6-disubstituted-2-arylbenzothiazoles via base-
induced cyclization/bromide displacement strategy has been
reported.
2-Arylbenzothiazoles are most commonly synthesized via
one of the two major routes. The most commonly used direct
method involves the condensation of ortho amino thiophenols
with substituted aldehydes, carboxylic acids, acyl chlorides,
and nitriles.2 This method, however, suffers from limitations
such as the difficulties encountered in the synthesis of readily
oxidizable 2-aminothiophenols bearing substituent groups.
Another route is based on the potassium ferricyanide
(Jacobson’s method) cyclization of thiobenzanilides.3
All the above routes to 2-arylbenzothiazoles except the
very first one need the precursor thiobenzanilides, whose
synthesis involves a multistep transformation.7 Therefore, a
new alternative route for the synthesis of 2-arylbenzothiazoles
needs to be explored. It was reasoned that ceric ammonium
(3) Shi, D. F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld,
P.; Fichtner, I.; Stevens, M. F. G. J. Med. Chem. 1996, 39, 3375-3384.
(4) Roe, A.; Tucker, W. P. J. Heterocycl. Chem. 1965, 2, 148-151.
(5) Stanetty, P.; Krumpak, B. J. Org. Chem. 1996, 61, 5130-5133.
(6) Spitulnik, M. J. Synthesis 1976, 730-731.
(7) Hutchinson, I.; Stevens, M. F. G.; Westwell, A. D. Tetrahedron Lett.
2000, 41 425-428.
(1) Bradshaw, T. D.; Wrigley, S.; Shi, D. F.; Schulz, R. J.; Paull, K. D.;
Stevens, M. F. G. Br. J. Cancer 1998, 77, 745-752.
(2) Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M. Tetrahedron Lett. 1997,
38, 6395, 6396.
10.1021/ol020027i CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/19/2002

nitrate (CAN), an excellent one-electron oxidant,8 can be
employed for radical generation and subsequent cyclization.
Accordingly, the thiophenols were treated with aromatic
nitriles in the presence of ceric ammonium nitrate, and as
envisaged the reactions proceed smoothly to afford the
corresponding 2-arylbenzothiazoles in excellent yield9 (Scheme
1).
Table 1. CAN-Mediated Synthesis of 2-Arylbenzothiazoles
R1
R2
R3
R4
yielda (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
CH3
F
Cl
H
H
Br
H
H
CH3
CH3
H
H
Cl
CF3
CF3
H
H
H
H
H
95
95
90
89
85
87
87
78
80
96
CH3O
CH3
CH3O
NO2
H
Cl
Br
H
CN
CH3O
H
Cl
H
H
I
Scheme 1
1j
H
a Yield refers to the pure isolated product.
containing a nitro functionality on the aryl ring underwent
decomposition rather than benzothiazole formation.
The results are summarized in Table 1. As shown in the
table, the synthesis of 2-arylbenzothiazoles bearing substit-
uents in both the benzothiazolyl and aryl rings is ac-
complished in excellent yield. It is further seen that 2-aryl-
benzothiazole bearing nitro functionality on the aryl ring
(entry 1e) is obtained in good yield by this method. This
contrasts, however, with the Bu3SnH/AIBN-promoted10 cy-
clization of aryl radical onto thioamides for the synthesis of
arylbenzothiazoles, where under these conditions thioamides
The usefulness of this methodology lies in the fact that
the reactions are carried out rapidly under extremely mild
conditions to give the product 2-arylbenzothiazoles (entries
1a-j) in excellent yield. Moreover, the method is compatible
with many substituents such as halogen, alkoxy, cyano, nitro,
etc. in the substrate. Unfortunately, the presence of an amino
substituent in the substrate leads to the quinone type product
via ready oxidation under reaction conditions rather than
benzothiazole formation. In conclusion, the methodology
reported herein is expected to be a quite general route for
the synthesis of a wide range of 2-arylbenzothiazoles.
(8) Molander, G. A. Chem. ReV. 1992, 92, 29-68.
(9) Experimental: All chemicals were of analytical grade. Solvents were
distilled before use. The products were characterized by their physical
constants and spectral analysis. Preparation of 7-methyl-2-(4-nitrophenyl)-
benzothiazole: O-thiocresol (0.248 g, 2 mmol), 4-nitrobenzonitrile (0.296
g, 2 mmol), and NaHCO3 (0.5 g) were dissolved in 20 mL of anhydrous
acetonitrile. Ceric ammonium nitrate (CAN) (2.192 g, 2 equiv) was added
to the above solution at room temperature under stirring. After 0.5 h
(attention: the yellow color of ceric ammonium nitrate disappeared) at room
temperature the mixture was filtered, washed with water, and extracted with
chloroform (3 × 10 mL). After drying over anhydrous Na2SO4, solvent
was evaporated under reduced pressure to give the product. The product
was purified by column chromatography (petroleum ether:ethyl acetate 9:1).
1H NMR (CDCl3): 2.53, (s, 3H), 7.10 (d, 1H), 7.34 (t, 1H), 7.83 (d, 1H),
7.20 (d, 2H), 8.27 (d,2 H). Anal. Calcd for C14H10N2O2S: C, 62.22; H,
3.76; N,10.38. Found: C, 62.19; H,3.56; N, 10.37.
Acknowledgment. I thank Dr B. P. Bandgar for his
extended cooperation and my wife Kalpana for her encour-
agement during this work.
Supporting Information Available: Experimental pro-
cedure, 1HNMR spectral data, and elemental microanalysis.
This material is available free of charge via Internet at
http://pubs.acs.org.
(10) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991, 47,
10119-10128.
OL020027I
1642
Org. Lett., Vol. 4, No. 10, 2002