One-pot tandem approach for the synthesis of benzothiazoles from benzyl halides

Article abstract of DOI:10.1055/s-0030-1258046

A one-pot tandem approach for the synthesis of benzothiazoles from benzyl halides and o-aminobenzenethiol was described. Benzothiazoles were obtained in high chemical yields under mild conditions in DMSO in the absence of an additional oxidant. Both benzy

Full text of DOI:10.1055/s-0030-1258046

LETTER
2457
One-Pot Tandem Approach for the Synthesis of Benzothiazoles from Benzyl
Halides
S
C
ynthesisof Be
n
h
f
e
romBenzyl
n
Halides Zhu, Takahiko Akiyama*
Department of Chemistry, Gakushuin University, 1-5-1, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax +81(3)59921029; E-mail: takahiko.akiyama@gakushuin.ac.jp
Received 23 June 2010
followed by the oxidation with a strong oxidant, such as
Abstract: A one-pot tandem approach for the synthesis of ben-
zothiazoles from benzyl halides and o-aminobenzenethiol was de-
scribed. Benzothiazoles were obtained in high chemical yields
8
8a,9
10
molecular O , H O ,
and MnO2, as described in
2
2
2
Scheme 1. Herein, we wish to describe a novel and
under mild conditions in DMSO in the absence of an additional ox- straightforward approach starting from benzyl halides and
idant. Both benzyl chlorides and bromides bearing a range of sub- o-aminobenzenethiol. Without having to use an additional
stituents proved to be suitable substrates.
oxidant, the tandem processes involving Kornblum oxida-
Key words: benzothiazole, benzyl halide, oxidation, one-pot, tan- tion, cyclization, and aromatization, furnished the 2-aryl
dem reaction
benzothiazoles in high yields.
CHO
COOH
NH2
SH
The benzothiazole moiety is an important architecture be-
cause of its widespread occurrence in biologically active
1
4
4
natural products and pharmaceuticals AW464
1
H+ or M+
4
O2 or H O2
2
(
Figure 1) has potent antitumor activity against renal and
2
colon cancer cells. Zopolrestat (2) is a highly efficacious
aldose reductase inhibitor (ARI). Investigational prodrug
4
3
N
S
X
?
MnO2
OH
3
has potent activity against human mammary tumor xe-
4
nografts. Thus, studies of benzothiazoles involving the
construction of various benzothiazole derivatives have
been extensively conducted.
X = Cl, Br
5
5
Scheme 1 Synthesis of benzothiazole 5 by condensation of o-ami-
nothiophenol 4
O
OH
At the outset, we designed the one-pot approach with ben-
zyl halides which presumably proceeded by way of corre-
sponding benzaldehydes generated in situ. As supposed in
N
N
Scheme 2, under the mild Kornblum oxidation conditions
O
F3C
N
S
N
11
S
(NaHCO , DMSO), the benzyl halide would be convert-
HO
3
O
ed into an aldehyde and this would be immediately
trapped by o-aminothiophenol to form a benzothiazoline.
Subsequently, the exposure of the benzothiazoline to the
same conditions would result in the formation of a ben-
1
2
Me
F
N
S
H
NH
O
(
CH2)4NH2
12
zothiazole via dehydrogenation. Remarkably, the com-
NH2 ⋅2HCl
bination of NaHCO and DMSO should be compatible
3
3
with all the processes.
With this idea in mind, we set out to examine the feasibil-
ity of the method. Initial treatment of o-aminothiophenol
Figure 1 Chemical structures of pharmaceutical molecules with
benzothiazole moiety
(
4) with benzyl chloride (6a, 1 equiv) in the presence of
NaHCO in DMSO at 90 °C afforded benzothiazole 5a in
a moderate yield. Gratifyingly, increasing the amount of
2
-Arylbenzothiazoles have been shown to possess anti-
3
microbial properties, and, in particular, to be active both
in vitro and in vivo against Mycobacterium tuberculosis.6
6a to 1.2 equivalents improved the chemical yield to 88%
3–15
(
Table 1, entry 1).1
Use of 1-chloromethylnaphthalene
One of the classic methods for the synthesis of 2-aryl ben-
gave the corresponding benzothiazole in 82% yield (entry
2). A range of substituted benzyl bromides gave the corre-
sponding benzothiazoles in high yields (entries 3–5). The
presence of the o-substituents did not interfere the reac-
tion (entries 6 and 7). Because of the side reaction involv-
ing the nucleophilic substitution between thiophenol and
zothiazoles 5 is the condensation of o-aminothiophenol 4
with aromatic carboxylic acids, or aromatic aldehydes,
7
SYNLETT 2010, No. 16, pp 2457–2460
x
x
.x
x
.2
0
1
0
Advanced online publication: 19.08.2010
DOI: 10.1055/s-0030-1258046; Art ID: U05910ST
©
Georg Thieme Verlag Stuttgart · New York

2
458
C. Zhu, T. Akiyama
LETTER
NaHCO3
DMSO
90 °C, 5 h
H
N
NaHCO3
DMSO
CHO
X
N
S
NH2
90 °C
S
X = Cl, Br
5
SH
Scheme 2 Supposed one-pot tandem approach from benzyl halides
Table 1 Generation of Benzothiazole 5 from Benzyl Chloride 6
NH2
Cl
NaHCO3
DMSO
R
+
N
S
R
SH
90 °C
6
4
5
Entry
1
Substrate
Product 5
Yield (%)a
88
N
Cl
Cl
5a
S
N
2
3
5b
5c
82
79
S
N
Cl
Cl
OMe
MeO
MeO
S
N
4
5
6
5d
5e
5f
83
82
82
S
N
OMe
Cl
S
N
Cl
S
N
S
Cl
7
5g
5h
78
45
N
S
Cl
8
Cl
Cl
a
Isolated yields.
aryl chloride, the corresponding benzothiazole was fur- In summary, we have developed an expedient and
nished in low chemical yield (entry 8).
straightforward approach for the synthesis of benzothiaz-
oles from benzyl halides. Eco-friendly and inexpensive
reagents were employed. Both benzyl chlorides and bro-
mides proved to be suitable substrates. A range of ben-
zothiazoles were furnished in high chemical yields
without having to use an additional oxidant. Other appli-
cations are ongoing.
Encouraged by the above results, we investigated the ap-
plicability of benzyl bromide. Several bromides were cho-
sen as representative examples (Table 2). In comparison
with benzyl chlorides, benzyl bromides gave slightly low
chemical yields. The benzene ring could be changed to a
1
-naphthyl or a 2-naphthyl group without compromising
the yield (entries 1–3). Even with various substituents on
the aromatic ring, the reaction proceeded smoothly with-
out any loss of reactivity (entries 4–6).
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science.
Synlett 2010, No. 16, 2457–2460 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzothiazoles from Benzyl Halides
2459
Table 2 Generation of Benzothiazole 5 from Benzyl Bromide 7
NaHCO3
NH2
N
S
R
Br
DMSO
R
+
90 °C
SH
7
5
4
Entry
1
Substrate
Product 5
Yield (%)a
N
S
Br
5a
85
80
Br
N
2
3
5b
5i
S
N
S
Br
86
N
Br
4
5
5c
5e
75
80
OMe
MeO
S
N
Br
S
N
Br
6
5f
76
S
a
Isolated yields.
References and Notes
(4) Bradshaw, T. D.; Westwell, A. D. Curr. Med. Chem. 2004,
1, 1241.
1
(
1) For selected examples, see: (a) Stevens, M. F. G.; McCall,
C. J.; Lelieveld, P.; Alexander, P.; Richter, A.; Davies, D. E.
J. Med. Chem. 1994, 37, 1689. (b) Aotsuka, T.; Abe, N.;
Fukushima, K.; Ashizawa, N.; Yoshida, M. Bioorg. Med.
Chem. Lett. 1997, 7, 1677. (c) Loaiza-Pérez, A. L.; Trapani,
V.; Hose, C.; Singh, S. S.; Trepel, J.; Stevens, M. F. G.;
Bradshaw, T. D.; Sausville, E. A. Mol. Pharmacol. 2002, 61,
(5) For recent reports, see: (a) Lewis, J. C.; Berman, A. M.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
2
493. (b) Nandurkar, N. S.; Bhanushali, M. J.; Bhor, M. D.;
Bhanage, B. M. Tetrahedron Lett. 2008, 49, 1045.
c) Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M.
(
Tetrahedron Lett. 2008, 49, 1598. (d) Chou, C.-H.; Yu,
P.-C.; Wang, B.-C. Tetrahedron Lett. 2008, 49, 4145.
13. (d) Trapani, V.; Patel, V.; Ciolino, H. P.; Yeh, G. C.;
(
e) Ma, H. C.; Jiang, X. Z. Synlett 2008, 1335. (f) Downer-
Riley, N. K.; Jackson, Y. A. Tetrahedron 2008, 64, 7741.
g) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org.
Hose, C.; Trepel, J. B.; Stevens, M. F. G.; Sausville, E. A.;
Loaiza-Pérez, A. L. Br. J. Cancer 2003, 88, 599. (e) Leong,
C. O.; Suggitt, M.; Swaine, D. J.; Bibby, M. C.; Stevens,
M. F. G.; Bradshaw, T. D. Mol. Cancer Ther. 2004, 3, 1565.
(
Lett. 2008, 10, 5147. (h) Pratap, U. R.; Mali, J. R.; Jawale,
D. V.; Mane, R. A. Tetrahedron Lett. 2009, 50, 1352.
(
f) Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci,
(
i) Miyaoku, T.; Mori, A. Heterocycles 2009, 77, 151.
L. S.; Jones, J. H.; Sawicki, D. R.; Srey, J.; Jacot, J. L.;
DiCioccio, A. T.; Petrova, T.; Sawicki, D. R.; Sredy, J.;
Jacot, J. L.; DiCioccio, A. T.; Petrova, T.; Mitschler, A.;
Podarny, A. D. J. Med. Chem. 2005, 48, 3141. (g) Huang,
S.-T.; Hsei, I.-J.; Chen, C. Bioorg. Med. Chem. 2006, 14,
(
j) Pal, S.; Patra, G.; Bhunia, S. Synth. Commun. 2009, 39,
1196. (k) Kumar, A.; Maurya, R. A.; Ahmad, P. J. Comb.
Chem. 2009, 11, 198. (l) Canivet, J.; Yamaguchi, J.; Ban, I.;
Itami, K. Org. Lett. 2009, 11, 1733. (m) Hachiya, H.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737.
6) (a) Logemann, W.; Galimberti, S.; Tosolini, G.; Carneri, I.;
Coppi, G. Farmaco Ed. Sci. 1961, 16, 795. (b) Prescott, B.;
Webb, J. M. Antibiot. Chemother. 1958, 8, 33. (c) Cossey,
H. D.; Gartside, R. N.; Stephens, F. F. Arzneim. Forsch.
6106. (h) Mortimer, C. G.; Wells, G.; Crochard, J.-P.; Stone,
(
(
E. L.; Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D.
J. Med. Chem. 2006, 49, 179.
(
2) (a) Bradshaw, T. D.; Matthews, C. S.; Cookson, J.; Chew,
E.-H.; Shah, M.; Bailey, K.; Monks, A.; Harrs, E.; Westwell,
A. D.; Wells, G.; Laughton, C. A.; Stevens, M. F. G. Cancer
Res. 2005, 65, 3911. (b) Mukherjee, A.; Bradshaw, T. D.;
Westwell, A. D.; Stevens, M. F. G.; Carmichael, J.; Martin,
S. G. Br. J. Cancer 2005, 92, 30.
1966, 16, 33.
7) (a) Chakraborti, A. K.; Selvam, C.; Kaur, G.; Bhagat, S.
Synlett 2004, 851. (b) Rudrawar, S.; Kondaskar, A.;
Chakraborti, A. K. Synthesis 2005, 2521. (c) Gupta, S. D.;
Singh, H. P.; Moorthy, N. S. H. N. Synth. Commun. 2007,
(
3) (a) Miyamoto, S. Exp. Opin. Ther. Patents 2002, 12, 621.
37, 4327. (d) Seijas, J. A.; Vazquez-Tato, M. P.; Carballido-
(b) Suzen, A.; Buyukbingol, E. Curr. Med. Chem. 2003, 10,
Reboredo, M. R.; Crecente-Campo, J.; Romar-Lopez, L.
Synlett 2007, 313. (e) Zhu, X.-Q.; Zhang, M.-T.; Yu, A.;
1329.
Synlett 2010, No. 16, 2457–2460 © Thieme Stuttgart · New York

2
460
C. Zhu, T. Akiyama
LETTER
Wang, C.-H.; Cheng, J.-P. J. Am. Chem. Soc. 2008, 130,
(12) For related study for the preparation of benzoxazoles, see:
Blacker, A. J.; Farah, M. M.; Marsden, S. P.; Saidi, O.;
Williams, J. M. J. Tetrahedron Lett. 2009, 50, 6106.
(13) Treatment of benzaldehyde with o-aminothiophenol under
the same reaction conditions gave the corresponding
benzothiazole in 80% yield.
2501. (f) Sharghi, H.; Asemani, O. Synth. Commun. 2009,
39, 860.
(
8) (a) Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A.
Heterocycles 2004, 62, 197. (b) Itoh, T.; Nagata, K.;
Ishikawa, H.; Ohsawa, A. Heterocycles 2004, 63, 2769.
(
c) Kawashita, Y.; Ueba, C.; Hayashi, M. Tetrahedron Lett.
006, 47, 4231. (d) Chen, Y.-X.; Qian, L.-F.; Zhang, W.;
(14) o-Aminophenol was not a suitable substrate and the
corresponding benzoxazole was furnished in low yield under
the same conditions.
2
Han, B. Angew. Chem. Int. Ed. 2008, 47, 9330.
(9) Bahrami, K.; Khodaei, M. M.; Naali, F. J. Org. Chem. 2008,
(15) General Experimental Procedure
73, 6835.
A mixture of benzyl halide (0.24 mmol, 1.2 equiv) with
(
(
10) Wilfred, C. D.; Taylor, R. J. K. Synlett 2004, 1628.
11) For seminal reports and reviews, see: (a) Kornblum, N.;
Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.;
Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79,
NaHCO (1 mmol, 5.0 equiv) in DMSO (2 mL) was stirred
3
for 5 h at 90 °C. Then, o-aminothiophenol (0.2 mmol, 1.0
equiv) was added into the above solution. Resulting solution
was continued stirring for overnight up to the completion of
the reaction. The reaction mixture was cooled to r.t. and was
extracted with EtOAc. The combined organic layers were
6562. (b) Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am.
Chem. Soc. 1959, 81, 4113. (c) Epstein, W. W.; Sweat, F.
W. Chem. Rev. 1967, 67, 247. (d)Mancuso, A. J.; Swern, D.
Synthesis 1981, 165. (e) Tidwell, T. T. Synthesis 1990, 857.
successively washed with H O and brine, dried over anhyd
2
Na SO , and concentrated to dryness. The crude product was
2
4
(
f) Tidwell, T. T. Org. React. 1990, 39, 297.
purified by preparative TLC on silica gel to give the product.
Synlett 2010, No. 16, 2457–2460 © Thieme Stuttgart · New York