One-pot preparation of 2 (alkly)arylbenzothiazoles from the corresponding o-halobenzanilides

Article abstract of DOI:10.1055/s-2007-984544

Thionation of o-halobenzanilides was carried out in the presence of Lawesson's reagent. Subsequently, the formed thioamides reacted with cesium carbonate to give the corresponding benzothiazole derivatives in the same pot. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984544

LETTER
2121
One-Pot Preparation of 2-(Alkyl)arylbenzothiazoles from the Corresponding
o-Halobenzanilides
O
ne-Pot Preparatio
a
nof
B
enzo
n
thiazoles
f
romthe
B
Corresponding
A
e
mides rnardi,*1 Lalla Aïcha Ba, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, Université Paul Verlaine-Metz,
1 Boulevard Arago, 57070 Metz, France
Fax +33(38)7315801; E-mail: kirsch@univ-metz.fr
Received 9 May 2007
of 2 stayed low, we envisaged changing the reaction con-
Abstract: Thionation of o-halobenzanilides was carried out in the
ditions. LR was first allowed to react with 1 in refluxing
toluene for three hours, and then Cs2CO3 was added to the
presence of Lawesson’s reagent. Subsequently, the formed thio-
amides reacted with cesium carbonate to give the corresponding
reaction mixture to obtain 2. Using this protocol and vary-
ing the amount of LR or Cs2CO3, 2 was obtained in a bet-
ter but still modest yield of 42% (entries 9 and 10). Next,
toluene was replaced by xylene to perform the reaction
(entry 11). The new protocol involved the thionation of 1
at 110 °C for about 2.5 hours (thionation monitored by
TLC) and the cyclization of 3 in refluxing xylene. Using
this sequence, 2 was then obtained in a good 74% yield.
benzothiazole derivatives in the same pot.
Key words: one-pot reaction, benzothiazole, cesium carbonate,
Lawesson’s reagent, cyclization
Benzothiazoles are broadly found in bioorganic and
medicinal chemistry with applications in drug discovery
and development for the treatment of tumors, diabetes,
epilepsy, inflammation, microbial infection, Parkinson’s
disease and find industrial applications as antioxidants
and vulcanization accelerators.2
The synthesis of 2-(alkyl)arylbenzothiazoles by the treat-
ment of various N-(acetyl)benzoyl-2-halogenoanilines7–11
and LR (0.6 equiv) in the presence of two equivalents of
Cs2CO3 in refluxing xylene was next examined. These re-
sults, summarized in Table 2, showed that the reaction
was efficient with different halogeno derivatives. The
thionation of the amides 4–10 took about two hours for
completion. In the case of amides 4–6, the cyclization step
was complete after five hours. The iodo derivative gave
the best yield in the case of these acetylated aniline deriv-
atives. In the case of amides 7–10, the time needed for
cyclization was between three and five hours. The fluoro
and iodo derivatives gave the shorter time of reaction, and
the iodo derivative led to the best yield in the case of these
benzoylated aniline derivatives.
There are various existing methods for the construction of
the benzothiazole moiety.3 During the course of a
medicinal chemistry project, we needed to prepare diverse
benzothiazoles. We focused our attention on the intra-
molecular nucleophilic aromatic substitution of o-halo-
thiobenzanilides (INASOB) promoted by a base.4 As for
the oxidative radical cyclization of thioanilides by the
treatment with potassium ferricyanide,5 INASOB re-
quired first the conversion of an amide into the corre-
sponding thioamide by using P4S10 or Lawesson’s reagent
(LR).4c,6 We reasoned that one-pot reaction from amides
should lead to the formation of benzothiazoles. The
present paper reports the synthesis of 2-(alkyl)aryl-
benzothiazoles using this strategy.
In summary, we have succeeded in the synthesis of 2-
(alkyl)arylbenzothiazoles by the reaction of the corre-
sponding N-(acetyl)benzoyl-2-halogenoanilines with LR
and Cs2CO3 via a one-pot reaction in refluxing xylene.12
To the best of our knowledge, this is the first time that this
sequence has been described. In these conditions, the thio-
amide generated in situ did not need to be isolated for
further cyclization. As a consequence, the global time of
reaction is decreased and the quantity of solvent needed
during this process is less than that usually needed in the
two-step reaction. Although the efficiency of the reaction
is greater with iodo and fluoro starting materials, the reac-
tion also worked well with chloro and bromo derivatives
which are less expensive and more easily available com-
pounds than the fluoro and iodo ones. The scope of the
reaction outlined is currently being explored in terms of
functional group tolerance.
In order to determine the optimized reaction conditions,
N-acetyl-2-bromoaniline7 (1) was allowed to react with
LR in the presence of a base under various reaction condi-
tions to obtain 2-methylbenzothiazole (2) and the results
are shown in Table 1. The reaction of 1 with LR in reflux-
ing organic bases (triethylamine, pyridine) only afforded
the corresponding thioamide 3 in good yields (entries 1
and 2). Next, the reaction was performed in refluxing tol-
uene as solvent. Bases such as pyridine, sodium carbon-
ate, potassium carbonate or cesium carbonate (Cs2CO3)
were used (entries 3–6). Only Cs2CO3 (entry 6) gave 2 in
a modest yield of 33%. Variation of the amount of LR or
Cs2CO3 did not improve the yield of 2 (entries 7 and 8).
As 1 was still present in the reaction medium and the yield
SYNLETT 2007, No. 13, pp 2121–2123
1
3
.0
8
.2
0
0
7
Advanced online publication: 27.06.2007
DOI: 10.1055/s-2007-984544; Art ID: D14107ST
© Georg Thieme Verlag Stuttgart · New York

2122
D. Bernardi et al.
LETTER
Table 1 One-Pot Cyclization of N-Acetyl-2-bromoaniline
Lawesson's reagent
H
H
N
N
base
N
S
solvent
+
S
O
Br
Br
1
2
3
Entry
LR (equiv)
Base (equiv)
Solvent (reflux)
Yield (%)a
1
2
3
1
2
1
–
pyridine
triethylamine
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
–
–
85
83
39
40
45
20
37
25
39
57
5
0.6
1
–
–
–
3
pyridine (2)
Na2CO3 (1.05)
K2CO3 (1.05)
Cs2CO3 (1.05)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (1.1)
Cs2CO3 (2)
40
44
44
20
19
17
–
–
4
0.6
0.6
0.6
1
–
5
–
6
33
21
41
42
30
74
7
8
0.6
0.6
1
9
10
11
–
0.6
–
a Yield after silica gel chromatography.
Table 2 Cyclization of Various N-(Acetyl)benzoyl-2-halogenoanilines
H
LR (0.6 equiv)
Cs2CO3 (2 equiv)
N
R
N
S
R
O
xylene
X
X = F, Cl, Br, I
R = Me, Ph
Compound R
X
Thionation
Cyclization
Yield (%)a
Temp (°C)
Time (h)
Temp
Time (h)
4
5
Me
Me
Me
Ph
F
105–115
105–115
105–115
105–115
105–115
105–115
105–115
2.5
2.5
2
reflux
reflux
reflux
reflux
reflux
reflux
reflux
5
5
5
3
5
4
3
77
68
79
84
72
81
87
Cl
I
6
7
F
2.5
2.5
2
8
Ph
Cl
Br
I
9
Ph
10
Ph
2.5
a Yield after silica gel chromatography.
(2) (a) Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71, 8261.
(b) Li, Y.; Wang, Y.; Wang, J. Chem. Lett. 2006, 35, 460.
(c) Chakraborti, A. K.; Rudrawar, S.; Kaur, G.; Sharma, L.
Synlett 2004, 1533; and references cited in these articles.
(3) (a) Ulrich, H. In Science of Synthesis, Vol. 11; Schaumann,
E., Ed.; Thieme: Stuttgart, 2001, 835–912. (b) Chakraborti,
A. K.; Selvam, C.; Kaur, G.; Bhagat, S. Synlett 2004, 851;
and references cited in these articles.
References and Notes
(1) Current address (postdoctoral fellow): Service de Marquage
Moléculaire et de Chimie Bioorganique, DSV/DBJC, CEA/
Saclay, 91191 Gif-sur-Yvette, France; email:
danbernardi@netcourrier.com, dan.bernardi@cea.fr.
Synlett 2007, No. 13, 2121–2123 © Thieme Stuttgart · New York

LETTER
One-Pot Preparation of Benzothiazoles from the Corresponding Amides
2123
(4) Sodium hydride: (a) Spitulnik, M. J. Synthesis 1976, 730.
(b) Mortimer, C. G.; Wells, G.; Crochard, J.; Stone, E. L.;
Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med.
Chem. 2006, 49, 179. (c) Van Zandt, M. C.; Jones, M. L.;
Gunn, D. E.; Geraci, L. S.; Jones, J. H.; Sawicki, D. R.;
Sredy, J.; Jacot, J. L.; DiCioccio, A. T.; Petrova, T.;
Mitschler, A.; Podjarny, A. D. J. Med. Chem. 2005, 48,
3141. Sodium methoxide: (d) Kim, J. S.; Sun, Q.; Gatto,
B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med.
Chem. 1996, 4, 621. (e) Yoshino, K.; Kohno, T.; Uno, T.;
Morita, T.; Tsukamoto, G. J. Med. Chem. 1986, 29, 820. (f)
Potassium carbonate: Hutchinson, I.; Stevens, M. F. G.;
Westwell, A. D. Tetrahedron Lett. 2000, 41, 425.
(5) (a) Lyon, M. A.; Lawrence, S.; Williams, D. J.; Jackson, Y.
A. J. Chem. Soc., Perkin Trans. 1 1999, 437. (b) Downer,
N. K.; Jackson, Y. A. Org. Biol. Chem. 2004, 2, 3039.
(6) Jesberger, M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929.
(7) Compounds 1, 4 and 5 were prepared according to literature
procedure: Ilies, M. A.; Vullo, D.; Pastorek, J.; Scozzafava,
A.; Ilies, M.; Caproiu, M. T.; Pastorekova, S.; Supuran, C. T.
J. Med. Chem. 2003, 46, 2187.
(9) Compound 7 was prepared according to literature procedure:
Chen, S.; Zhang, X.; Ma, H.; Lu, Y.; Zhang, Z.; Li, H.; Lu,
Z.; Cui, N.; Hu, Y. J. Organomet. Chem. 2005, 690, 4184.
(10) Compounds 8 and 9 were prepared according to literature
procedure: Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71,
1802.
(11) Compound 10 was prepared according to literature
procedure: Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7,
4777.
(12) Typical Procedure: In a 10-mL flask were placed the
appropriate amide (1.17 mmol), Lawesson’s reagent13 (0.6
equiv, 0.29 g), xylene (3 mL) and a magnetic stirring bar.
The mixture was stirred under argon at 105–115 °C for 2.5 h.
Then Cs2CO3 (2 equiv, 0.81 g)was added and the reaction
mixture was stirred under reflux for the indicated time. The
solvent was evaporated to dryness and the crude product was
chromatographed on silica gel (cyclohexane–EtOAc, 97:3)
to afford the desired benzothiazole derivative.
(13) During this study we used commercial and synthesized LR,
prepared according to the literature procedure: Pedersen, B.
S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. Bull. Soc.
Chim. Belg. 1978, 87, 223.
(8) Compound 6 was prepared according to literature procedure:
Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 10546.
Synlett 2007, No. 13, 2121–2123 © Thieme Stuttgart · New York

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