An efficient palladium catalyzed synthesis of 2-arylbenzothiazoles

Article abstract of DOI:10.1016/j.tetlet.2003.09.138

A novel and convergent palladium catalyzed synthesis of 2-arylbenzothiazoles has been investigated. The key step in the synthesis is a Suzuki biaryl coupling of 2-bromobenzothiazole with aryl boronic acids to provide a variety of 2-arylbenzothiazole derivatives in good yield. The synthetic utility of this methodology is demonstrated by the synthesis of 2-(4-aminophenyl)-6-methoxybenzothiazole, a PET probe precursor for the in vivo imaging of Alzheimer's disease.

Full text of DOI:10.1016/j.tetlet.2003.09.138

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8535–8537
An efficient palladium catalyzed synthesis of 2-arylbenzothiazoles
Vattoly J. Majo, Jaya Prabhakaran, J. John Mann* and J. S. Dileep Kumar*
Department of Psychiatry/Neuroscience, NYSPI/Columbia University, 1051 Riverside Drive, New York, NY 10032, USA
Received 20 August 2003; revised 17 September 2003; accepted 17 September 2003
Abstract—A novel and convergent palladium catalyzed synthesis of 2-arylbenzothiazoles has been investigated. The key step in the
synthesis is a Suzuki biaryl coupling of 2-bromobenzothiazole with aryl boronic acids to provide a variety of 2-arylbenzothiazole
derivatives in good yield. The synthetic utility of this methodology is demonstrated by the synthesis of 2-(4-aminophenyl)-6-
methoxybenzothiazole, a PET probe precursor for the in vivo imaging of Alzheimer’s disease.
© 2003 Elsevier Ltd. All rights reserved.
2-Arylbenzothiazoles are an important class of com-
pounds owing to their potent utility as imaging agents
for b-amyloid, antitumor agents, antituberculotics,
antiparasitics, calcium channel antagonists, chemilu-
minescent agents and also as photosensitizers.1–7 The
reported syntheses of 2-arylbenzothiazoles involve the
condensation of 2-aminobenzenethiol with 4-substituted
phenyl derivatives of nitrile, aldehyde, acid, acid chlo-
rides or esters and by the use of Jacobson’s cyclization
of thiobenzanilides.8–10 Other general methods include
microwave mediated reaction of o-aminothiophenol
with b-chlorocinnamaldehydes, reaction of dibenzyl
disulfides with o-aminothiophenol, reduction of o,o%-
dinitrodiphenyl disulfide, reaction of S-aryl thioben-
zoate with arylhaloamines, from 1,2,3-benzodithia-
zole-2-oxides, radical cyclization of benzyne intermedi-
ates and Grignard reactions of arylisothiocyanates.11–16
However, most of the above methods require multistep
synthesis and therefore, we have sought to develop a
convergent strategy for the synthesis of 2-arylbenzothi-
azoles. Our method utilizes a Suzuki cross coupling of
the common intermediates 2-bromobenzothiazole (1)
and 2-bromo-6-methoxybenzothiazole (2) with various
aryl boronic acids/ esters as the key step (Table 1).
Since a wide variety of aryl boronic acids are commer-
cially available, or can be easily prepared from the
corresponding bromides,17 this methodology would
offer a higher degree of flexibility with regard to func-
tional groups that can be placed on the 2-aryl moiety,
thereby providing a better understanding of the struc-
ture activity relationship (SAR) of the target com-
pounds.
Benzothiazole was brominated using nBuLi and CBr4
to provide corresponding 2-bromo benzothazole (1) in
60% yield.18 2-bromo-6-methoxybenzothiazole (2)
(65%) was synthesized by Sandmayer reaction of 2-
amino-6-methoxybenzothiazole by heating with isoamyl
nitrite and CuBr2 in presence of PEG.19 The biaryl
coupling was initially attempted with 1 and phenyl-
boronic acid under the optimized reaction condition
using Pd2(dba)3 in DME-water with aqueous K2CO3 to
provide 2-phenylbenzothiazole (4a) in 50% yield.20
Under identical conditions, coupling of 1 and 2 with
4-acetylboronic acid, 4-aminophenylboronic ester, Boc
protected
4-aminophenylboronic
ester,
3-thio-
pheneboronic acid and 2-napthaleneboronic acid pro-
vided the corresponding 2-arylbenzothiazole derivatives
in moderate to good yield (Table 1). Benzothiazole
derivative 4i and its demethylated analogue are
positron emission tomography (PET) probe precursors
for the in vivo quantification of b-amyloid.1,21 How-
ever, our attempts to couple 2,4-dimethoxyphenyl-
boronic acid with 1 did not afford the desired product
probably due to steric hindrance, dehydroboronation of
the boronic acid and recovery of 1 was the major
process observed under the optimized reaction
conditions.
In summary, we have utilized a novel chemistry of
2-bromobenzothiazoles for the facile synthesis of 2-
arylbenzothiazoles using Suzuki biaryl coupling. The
synthetic utility of these reactions are demonstrated by
the one step synthesis of 2-amino-6-hydroxyben-
zothazole, a potent PET probe precursor for the in vivo
imaging of b-amyloid. Future work will be undertaken
to develop a combinatorial version of this synthesis for
the SAR of 2-arylbenzothiazoles for various pharma-
ceutical applications.
Keywords: boronic acid; benzothiazole; Suzuki coupling; palladium.
* Corresponding author. Fax: +212-543-6017; e-mail: dk2038@
columbia.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.138

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V. J. Majo et al. / Tetrahedron Letters 44 (2003) 8535–8537
Table 1. Biaryl coupling of 2-bromobenzothazole (1) and 2-bromo-6-methoxy benzothiazole (2) with various boronic acids
and esters
Kato, E.; Oya, M.; Iso, T.; Iwao J. Med. Chem. 1983, 31
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