One-step synthesis of 2-arylbenzothiazole ('BTA') and -benzoxazole precursors for in vivo imaging of β-amyloid plaques

Article abstract of DOI:10.1016/j.tetlet.2004.12.111

We report the simple and efficient synthesis of 2-arylbenzothiazoles ('BTA') and 2-arylbenzoxazoles by direct coupling of benzothiazoles or benzoxazoles with aryl bromides. This method permits direct one-step access to precursors of radiolabeled BTA-1 and

Full text of DOI:10.1016/j.tetlet.2004.12.111

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1349–1351
One-step synthesis of 2-arylbenzothiazole (‘BTA’) and
-benzoxazole precursors for in vivo imaging of b-amyloid plaques
David Alagille,a Ronald M. Baldwina and Gilles D. Tamagnana,b,
*
aYale University and VA CT HCS, Department of Psychiatry, 333 Cedar Street, New Haven, CT 06510, USA
bInstitute for Neurodegenerative Disorders, 60 Temple Street, Suite 8B, New Haven, CT 06510, USA
Received 22 September 2004;accepted 21 December 2004
Available online 12 January 2005
Abstract—We report the simple and efficient synthesis of 2-arylbenzothiazoles (ÔBTAÕ) and 2-arylbenzoxazoles by direct coupling of
benzothiazoles or benzoxazoles with aryl bromides. This method permits direct one-step access to precursors of radiolabeled BTA-1
and BTA-2 and their 6-methoxy analogues, used for in vivo imaging of b-amyloid plaques with positron emission tomography
(PET).
Ó 2004 Elsevier Ltd. All rights reserved.
AlzheimerÕs disease (AD) is a member of a heteroge-
neous family of diseases referred to as amyloidosis,
including type II diabetes, variant Creutzfeldt-Jakob
disease, painful joints associated with long-term hemo-
dialysis, and rare cases of hereditary insomnia.1 In all
of these disorders, proteins that are normally soluble
are converted into insoluble aggregates that can form
intractable and frequently toxic deposits in skeletal mus-
cular tissue and in organs such as heart, liver, and
brain.2 In vivo biomarkers of amyloid deposits in the
brain would be useful to identify and follow individuals
at risk for AD and to assist the evaluation of new anti-
amyloid therapies under development.3,4 A large num-
ber of radiolabeled compounds have been investigated
as radioactive amyloid agents5–11 for imaging amyloid
plaque by positron emission tomography (PET). The
2-arylbenzothiazole (BTA) derivatives represent one of
the most promising families.8,12 The reported synthesis
of 2-arylbenzothiazoles have commonly used one of
two methods: condensation of ortho-amino thiophenols
with substituted aldehydes, carboxylic acids, acyl chlo-
rides, or nitriles;12 or JacobsonÕs cyclization of thiobenz-
anilides mediated by potassium ferricyanide.12 Yields
from these methods are relatively low and the condensa-
tion method also has the limitation of a readily oxidiz-
able sulfur group. Recently, Majo et al.13 reported
Suzuki cross-coupling between 2-bromobenzothiazoles
and boronic acids or esters however, the moderate to
low yield and scarcity of commercially available boronic
acids/esters limit the use of this reaction despite the
remarkable advantage of a one-step synthesis. The same
year, Yokooji et al.14 reported the direct arylation of
thiazoles with aryl bromides in the presence of
Pd(OAc)2/P(t-Bu)3 and they extended this reaction to a
very small number of benzothiazoles. In this letter, we
describe extending the potential application of the direct
coupling between benzothiazole 1 or 6-methoxybenzo-
thiazole 2 and aryl bromides with the objective of a
one-step synthesis of precursors to radiotracers for
imaging amyloid plaques in vivo.
Benzothiazole 1 or 6-methoxybenzothiazole 2 was
reacted at 150 °C in a sealed tube with aryl bromide in
DMF in the presence of Pd(OAc)2, Cs2CO3, and CuBr
with P(t-Bu)3 as ligand19 yielding after 1–3 h of reaction
the desired 2-arylbenzothiazole in 66–84% yield (Table
1). In contrast with the Suzuki cross-coupling, this
method permitted direct synthesis in good yield of 2-
(2,4-dimethoxyphenyl)benzothiazole 5f and its 6-meth-
oxy analogue 5m. This reaction allows us to obtain in
good yield and in one-step (no protection of the nitrogen
required) the BTA-1 and BTA-2 precursors (5b and 5c)
as well as their 6-methoxy analogues (5h and 5i). Reac-
tion of the 4-bromo-N-Boc protected aniline led to the
deprotected compound by thermal cleavage of the N-
Boc group as the major product. To conclude this work
Keywords: 2-Arylbenzothiazole;BTA;2-Arylbenzoxazole;Amyloid
plaques;Palladium;Direct coupling.
*
Corresponding author. Tel.: +1 2034014309;fax: +1 2037892119;
e-mail: gtamagnan@indd.org
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.111

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D. Alagille et al. / Tetrahedron Letters 46 (2005) 1349–1351
Table 1. Direct coupling of 1–3 with aryl bromides
Pd(OAc)2 / P(t-Bu)3
Y
Y
Cs2CO3 / CuBr
X
X
N
+
Ar Br
H
Ar
DMF, 150oC, 1h
N
X = S, Y = H,
1
4a-f
5a-p
X = S, Y = OMe 2
X = O, Y = H,
3
Benzazole
Aryl bromide
Product
Yielda
79
Suzuki yieldb
48
1
5a
F
1
1
5bc
68
71
—
—
NH2
NH
5cc
BAT-1
1
1
1
5d
BAT-2
78
—
—
0
N
5b (NH2)
5e (NHBoc)
63
8
NHBoc
O
5f
84
O
2
2
2
5g
71
66
78
54
35
—
F
5hc
NH2
NH
5ic
6-OMe-BAT-1
2
2
5j
6-OMe-BAT-2
78
—
N
5h (NH2)
5k (NHBoc)
68
10
—
55
NHBoc
O
2
5m
77
—
O
3
3
5nc
5o
70
72
NH2
N
O
3
5p
64
O
The reaction was carried out using Pd(OAc)2-P(t-Bu)3 (0.05 and 0.1 equiv to benzothio- or benzoxazole), Cs2CO3 (1 equiv) and CuBr (0.2 equiv) in
DMF, sealed tube at 150 °C for 1 h unless otherwise noted.19
a Yield refers to pure isolated product.
b Previously published yield shown here for comparison.13
c Reaction time was extended to 3 h.
we investigated the possible application of this method-
ology to the synthesis of 2-arylbenzoxazoles, even
though the synthesis of such compounds is well de-
scribed in the literature by other synthetic means (oxida-
tive cyclization of phenolic SchiffÕs bases15,16 or coupling
of 2-aminophenols with carboxylic acids17,18). In the
same manner as benzothiazole, benzoxazole 3 react with
aryl bromide to provide after 1 h at 150 °C the desired 2-
arylbenzoxazole (Table 1).
In summary, we report a simple and efficient synthesis
of 2-arylbenzothiazoles and 2-arylbenzoxazoles using a

D. Alagille et al. / Tetrahedron Letters 46 (2005) 1349–1351
1351
Y.;Huang, G.-F.;Debnath, M. L.;Klunk, W. E. Bioorg.
Med. Chem. Lett. 2002, 12, 295.
9. Zhuang, Z.-P.;Kung, M.-P.;Hou, C.;Plossl, K.;Skov-
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direct palladium-catalyzed arylation of benzothiazoles
or benzoxazoles with aryl bromides. This methodology
permits the direct synthesis of precursors to radiotracers
for the imaging of amyloid deposit in vivo and allows
the development of
benzothiazoles.
a
large library of 2-aryl-
10. Zhuang, Z. P.;Kung, M. P.;Wilson, A.;Lee, C. W.;
Plossl, K.;Hou, C.;Holtzman, D. M.;Kung, H. F.
Med. Chem. 2003, 46, 237.
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13. Majo, V. J.;Prabhakaran, J.;Mann, J. J.;Kumar, J. S. D.
Tetrahedron Lett. 2003, 44, 8535.
This work was supported in part by the National Insti-
tutes of Health (DA16180-01) and from Department of
Veterans Affairs, National Center for PTSD Alcohol
Research.
14. Yokooji, A.;Okazawa, T.;Satoh, T.;Miura, M.;Nomura,
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