Oxidative cyclization of thiobenzanilides to benzothiazoles using N-Benzyl-DABCO tribromide under mild conditions

Article abstract of DOI:10.1055/s-2005-869841

N-benzyl-DABCO tribromide, a stable, crystalline organic ammonium tribromide (OATB), have been used as an alternative electrophilic bromine source for the efficient oxidative cyclization of thiobenzanilides to the corresponding benzothiazoles under mild conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869841

1612
LETTER
Oxidative Cyclization of Thiobenzanilides to Benzothiazoles Using N-Benzyl-
DABCO Tribromide under Mild Conditions
O
xidative Cyc
i
lization
r
of
T
hio
o
benzanilides
uto Benzothi
zzoles Matloubi Moghaddam,* Hassan Zali Boeini
Sharif University of Technology, Department of Chemistry, PO Box 11365-9516 Tehran, Iran
E-mail: matloubi@sharif.edu
Received 4 March 2005
use of liquid bromine, which is a highly toxic and corro-
Abstract: N-benzyl-DABCO tribromide, a stable, crystalline or-
ganic ammonium tribromide (OATB), have been used as an alterna-
tive electrophilic bromine source for the efficient oxidative
cyclization of thiobenzanilides to the corresponding benzothiazoles
under mild conditions.
sive reagent, and can be difficult to manipulate on small
scale. It is known for the Hugerschoff reaction that excess
bromine will produce the perbromide of the amino-
benzothiazole, which can then brominate the benzene ring
under prolonged reaction conditions.
Key words: benzothiazole, N-benzyl-DABCO-tribromide, oxida-
tive cyclization
As an alternative reagent to liquid bromine, organic am-
monium tribromides (OATBs) such as benzyltrimethyl-
ammonium tribromide and tetrabutylammonium tri-
bromide, which are of high molecular weight, stable,
crystalline solids, are capable of delivering a stoichiomet-
ric amount of bromine where small amounts of bromine
are necessary for microscale reactions. Benzyltrimethyl-
ammonium tribromide has been successfully used for the
conversion of substituted aryl thioureas to the correspond-
ing 2-aminobenzothiazoles.18 However, this reaction is
limited to N,N-dialkylaminothiourea derivatives. The
asymmetric N,N¢-diarylthiourea derivatives could lead to
two different products.
Benzothiazole derivatives are widely found in bioorganic
and medicinal chemistry with applications in drug discov-
ery and development for treatment of autoimmune and in-
flammatory diseases,1 in the prevention of solid organ
transplant rejection, epilepsy,2–4 amyotrophic lateral scle-
rosis,5 analgesia,6 tuberculosis,7 viral infections8, and can-
cer.9,10 They have also found applications in industry as
antioxidants,11 vulcanization accelerators,12 and as a
dopant in a light emitting organic electroluminescent de-
vice.13
Herein we report a new and efficient route for the synthe-
sis of 2-arylbenzothiazoles with different substituents on
the two aromatic rings. When thiobenzanilide is dissolved
in a suitable solvent and treated with equimolar amount of
an organic ammonium tribromide, rapid and efficient ox-
idative cyclization to the corresponding 2-arylbenzothia-
zole derivatives takes place. To the best of our knowledge
this reaction has not been reported previously (Scheme 2).
NH2
SH
[pmIm]Br
N
S
+
R
RCHO
MW 3–5 min
Scheme 1
Therefore several attempts towards the synthesis of
substituted benzothiazoles have been reported in the liter-
ature. Recently, a one-step condensation of 2-amino-
thiophenol with aromatic aldehydes in an ionic liquid
medium and under microwave irradiation has been used
for the preparation of 2-arylbenzothiazoles (Scheme 1).14
Despite good yields and low reaction times, this reaction
is limited to 2-arylbenzothiazoles having different substi-
tutes on the aryl moiety and uses rather expensive starting
materials. An old method uses potassium hexacyanofer-
rate for oxidative cyclization of heteroaryl thiobenzanil-
ides to corresponding benzothiazoles.15
R
S
R
S
N
OATB
R'
N
H
CH2Cl2 / CCl4
R'
Scheme 2
In order to find the optimum conditions for this reaction,
different OATBs and various solvents were examined.
The effects of different solvents in this reaction were also
investigated. The model compound 1 was reacted with
one molar equivalent of PhCH2NEt3Br3 (Table 1, entry 1)
in a mixture of CH2Cl2–CCl4 (50:50) at room temperature
for 30 minutes to give the desired product 2 in 70% yield.
Dichloromethane itself was also found to be effective
(Table 1, entry 2). Acetic acid, which has been used effec-
tively for oxidative cyclization of thioureas, was not suit-
able for this reaction (Table 1, entry 4). Other polar
solvents such as dimethylformamide, and methanol gave
little (<10%) product (Table 1, entry 3, 5).
Another alternative for the synthesis of 2-substituted ben-
zothiazoles is the Hugerschoff reaction, which consists of
the oxidative cyclization of arylthioureas to 2-aminoben-
zothiazoles with liquid bromine in chloroform.16,17 Al-
though this reaction usually proceeds efficiently at room
temperature, several drawbacks are associated with the
SYNLETT 2005, No. 10, pp 1612–1614
Advanced online publication: 12.05.2005
DOI: 10.1055/s-2005-869841; Art ID: D05905ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
6
.2
0
0
5

LETTER
Oxidative Cyclization of Thiobenzanilides to Benzothiazoles
1613
Table 1 Variation of Solvent in the Oxidative Cyclization of
Thiobenzanilide with PhCH2NEt3Br3
References
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2587.
S
PhCH2NEt3Br3
(1 mol equiv)
S
N
H
N
solvent
(2) Hays, S. J.; Rice, M. J.; Ortwine, D. F.; Johnson, G.;
Schwarz, R. D.; Boyd, D. K.; Copeland, L. F.; Vartanian, M.
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Ganil, P.; Gueremy, C.; Honore, E.; Just, B.; Kerphirique,
R.; Gontier, S.; Hubert, P.; Laduron, P. M.; Le Blevec, J.;
Meunier, M.; Miquet, J. M.; Nemecek, C.; Pasquet, M.; Piot,
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(4) He, Y.; Benz, A.; Fu, T.; Wang, M.; Covey, D. F.; Zorumski,
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(5) Bensimon, G.; Lacomblez, L.; Meininger, V. New Engl. J.
Med. 1994, 330, 585.
(6) Foscolos, G.; Tsatsas, G.; Champagnac, A.; Pommier, M.
Ann. Pharm. Fr. 1977, 35, 295.
(7) Shirke, V. G.; Bobade, A. S.; Bhamaria, R. P.; Khadse, B.
G.; Sengupta, S. R. Indian Drugs 1990, 27, 350.
(8) Paget, C. J.; Kisner, K.; Stone, R. L.; Delong, D. C. J. Med.
Chem. 1969, 12, 1016.
(9) Gong, B.; Hong, F.; Kohm, C.; Bonham, L.; Klein, P.
Bioorg. Med. Chem. Lett. 2004, 14, 1455.
(10) Hutchinson, I.; Bradshaw, T. D.; Matthews, C. S.; Stevens,
M. F. G.; Westwell, A. D. Bioorg. Med. Chem. Lett. 2003,
13, 471.
2
1
Entry
Solvent
Reaction conditions
Yield (%)
63
1
2
3
4
5
CH2Cl2–CCl4
CH2Cl2
DMF
r.t./20 min
r.t./20 min
r.t./2 h
57
<10
<10
<5
AcOH
r.t./2 h
MeOH
r.t./2 h
The effects of three different OATBs in the reaction
course was also examined and it was found that com-
pound N-benzyl-DABCO-tribromide19 gave higher yields
and the reaction proceeded in shorter time (Table 2).
The thiobenzanilide derivatives used in this study were
prepared by reacting the appropriate benzanilides with
P2S5 in THF at room temperature. Also some of thio-
benzanilides having a nitrogen heterocycle were prepared
by the Willgerodt–Kindler reaction of quinaldine with
aromatic amines under microwave irradiation.20 The gen-
erality of our procedure has been shown by the successful
conversion of eight quite different substrates to the
corresponding benzothiazoles (Table 3). This method was
also successfully used for the bis-oxidative cyclization
of bisthiobenzanilides to diaryl thiazolobenzothiazoles
(Table 3, entry 8).
(11) Ivanov, S. K.; Yuritsyn, V. S. Neftekhimiya 1971, 11, 99;
Chem. Abstr. 1971, 74, 124487m.
(12) Monsanto, Co. Brit. Pat. 1,106,577, 1968; Chem. Abstr.
1968, 68, 96660t.
(13) Zhang, X. H.; Wong, O. Y.; Gao, Z. Q.; Lee, C. S.; Kwong,
H. L.; Lee, S. T.; Wu, S. K. Mater. Sci. Eng., B 2001, 85,
182.
(14) Ranu, B. C.; Jana, R.; Dey, S. S. Chem. Lett. 2004, 33, 274.
(15) (a) Schwartz, H. Neth. Appl. 6,607,039, 1966. (b) Osuka,
A.; Uno, Y.; Horiuchi, H.; Suzuki, H. Synthesis 1984, 145.
(c) Saikachi, H.; Hisano, T. Chem. Pharm. Bull. 1960, 8, 51.
(d) Compare: Saikachi, H.; Hisano, T. Chem. Pharm. Bull.
1959, 7, 716.
In conclusion, we have developed a new versatile method
for the one-pot preparation of benzothiazoles via the mild
oxidative cyclization of corresponding thiobenzanilides
with organic ammonium tribromides.
(16) (a) Hugerschoff, H. Chem. Ber. 1901, 34, 3130.
(b) Hugerschoff, H. Chem. Ber. 1903, 36, 3121.
Table 2 Variation of OATBs in the Oxidative Cyclization of Thiobenzanilide
S
S
N
OATB (1 mol equiv)
CH2Cl2:CCl4 (50:50)
N
H
Entry
OATB
Reaction conditions
r.t./20 min
Yield (%)
1
2
3
PhCH2NMe3Br3
60
63
70
PhCH2NEt3Br3
r.t./20 min
r.t./15 min
N
N
_
Ph
Br3
+
Synlett 2005, No. 10, 1612–1614 © Thieme Stuttgart · New York

1614
F. Matloubi Moghaddam, H. Zali Boeini
LETTER
Table 3 Oxidative Cyclization of Thiobenzanilides to the 2-Arylbenzothiazoles21
S
N-benzyl-DABCO tribromide
Ar'
2-arylbenzothiazoles
Ar
N
CH2Cl2/CCl4 (1:1)
r.t. 15–30 min
H
Entry
1
Ar
Ph
Ar¢
Producta
Time (min)b Mp
Mp (lit.)
Yield (%)c
70
Ph
S
15
30
30
112–114
113–11415a
N
S
2
3
p-ClPh
Ph
116–117
139–141
117–11815a
140–14115a
72
58
Cl
N
Ph
p-ClPh
Cl
S
N
S
4
5
Ph
Ph
p-MePh
25
30
131–134
109–110
–
75
70
Me
N
S
2-Naphthyl
109–11015b
N
6
7
8
2-Quinolyl Ph
20
25
30
198–199
218–220
227–229
198–20015c
220–22115c
–
65
67
40
S
N
N
2-Quinolyl p-MePh
S
Me
N
N
Ph
2-(Benzothioyl
amino)phenyl
S
S
N
N
a All products were characterized by melting points, IR, 1H NMR and their spectroscopic data were similar to those reported in the literature.21
b The reaction times were optimized after several experiments.
c All yields refer to isolated products.
(17) Sprague, J. M.; Land, A. H. In Heterocyclic Compounds,
Vol. 5; Eldrenfield, R. C., Ed.; J. Wiley: New York, 1958,
Chap. 8, 484–721.
(18) Jordan, A. D.; Luo, C.; Reitz, A. B. J. Org. Chem. 2003, 68,
8693.
(19) Preparation of N-Benzyl-DABCO Tribromide.
To a stirred solution of DABCO (50 mmol) in dioxane (50
mL), a solution of benzyl bromide (50 mmol) in dioxane (5
mL) was added slowly for about 20 min. Then, a solution of
bromine (50 mmol) in dioxane (20 mL) was cautiously
added under vigorous stirring. After cooling the solution, the
resulting orange crystals were filtered and dried at r.t.
(20) Matloubi Moghaddam, F.; Zali Boeini, H.; Taheri, S. J.
Sulfur Chem. 2004, 25, 407.
(21) General Procedure for the Oxidative Cyclization of
Thiobenzanilides.
To a stirred solution of thiobenzanilide (1 mmol) in CH2Cl2–
CCl4 (50:50, 8 mL), OATB (1.1 mmol) was added. The
reaction mixture was stirred for 20 min at r.t. and the solvent
removed under reduced pressure. The residue was subjected
to column chromatography (EtOAc–hexane, 1:5, silica gel)
to obtain pure colorless product.
Selected spectroscopic data for compounds 4, 5, 8.
Compound 4: 1H NMR: d = 8.28 (d, J = 7.3 Hz, 2 H), 8.16
(d, J = 8.2 Hz, 1 H), 7.31 (s, 1 H), 7.15–7.22 (m, 3 H), 7.09
(d, J = 8.2 Hz, 1 H).
Compound 5: 1H NMR: d = 8.96 (d, J = 7.8 Hz, 1 H), 8.17
(d, J = 7.0 Hz, 2 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.75 (d, J = 8.6
Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H),
7.48 (t, J = 7.5 Hz, 1 H), 7.36–7.41 (m, 3 H).
Compound 8: 1H NMR: d = 8.31 (s, 2 H), 7.21–7.36 (m, 10
H).
Synlett 2005, No. 10, 1612–1614 © Thieme Stuttgart · New York