Straightforward synthesis of PET tracer precursors used for the early diagnosis of Alzheimers disease through Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2013.06.085

In positron emission tomography [¹¹C]PIB, Pittsburgh Compound-B, is currently the most widely used radiopharmaceutical for the early diagnosis of Alzheimer's disease. Synthetic routes for the preparation of the precursor of [¹¹C]PIB are reported in the literature. These strategies require multiple steps and the use of protecting groups. This paper describes a simple one-step synthesis of the precursor of [¹¹C]PIB through a Suzuki-Miyaura coupling reaction using thermal conditions or microwave activation. These methods were successfully applied to the synthesis of various 2-arylbenzothiazole and 2-pyridinylbenzothiazole compounds including [ ¹⁸F] precursor derivatives of PIB containing a nitro function.

Full text of DOI:10.1016/j.tet.2013.06.085

Tetrahedron 69 (2013) 7345e7353
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
Straightforward synthesis of PET tracer precursors used for the early
diagnosis of Alzheimers disease through SuzukieMiyaura
cross-coupling reactions
*
ꢀ
Guillaume Bort, Maite Sylla-Iyarreta Veitía , Clotilde Ferroud
ꢀ
ꢀ
Conservatoire national des arts et metiers, ERL 3193 Cnrs, 2 rue Conte, 75003 Paris, France
a r t i c l e i n f o
a b s t r a c t
In positron emission tomography [11C]PIB, Pittsburgh Compound-B, is currently the most widely used
radiopharmaceutical for the early diagnosis of Alzheimer’s disease. Synthetic routes for the preparation
of the precursor of [11C]PIB are reported in the literature. These strategies require multiple steps and the
use of protecting groups. This paper describes a simple one-step synthesis of the precursor of [11C]PIB
through a SuzukieMiyaura coupling reaction using thermal conditions or microwave activation. These
methods were successfully applied to the synthesis of various 2-arylbenzothiazole and 2-
pyridinylbenzothiazole compounds including [18F] precursor derivatives of PIB containing a nitro
function.
Article history:
Received 6 May 2013
Received in revised form 18 June 2013
Accepted 20 June 2013
Available online 29 June 2013
Keywords:
Cross-coupling
Palladium
SuzukieMiyaura
Alzheimer’s disease
Pittsburgh Compound-B
PIB
Ó 2013 Elsevier Ltd. All rights reserved.
Positron emission tomography
PET
1. Introduction
start of the disease, but also a relevant follow-up of drugs tested.7
The ‘amyloid hypothesis’,8 today well accepted by the scientific
Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder responsible for 60%e70% of dementia cases. About 6% of
the population aged 65 and older suffer from dementia, which
represented 36 million people worldwide in 2010 with a total so-
cietal cost estimated to be US$ 604 billion. The number of AD pa-
tients is believed to double every 20 years to potentially reach 115
million in 2050.1 AD has both human and economical impacts on
our society and is expected to become one of the major health care
problems for industrialized countries in the future.2 As a matter of
fact the research for a treatment and an early diagnosis of AD, with
in vivo imaging of amyloid plaques as the most promising tech-
nique,3 appears today as a priority.4
In the last 20 years, the research on AD focused on the de-
velopment of different therapeutic approaches and diagnostic
techniques to detect the pathology at an early stage.5 However, to
date the definitive diagnosis of AD can be performed post-mortem
only.6 An early diagnosis of AD would not only allow an in-
tervention with future disease-modifying therapies right from the
community, suggest that Ab plaques appear in the brain 10e20
years before the clinical symptoms of AD. In vivo methods for
amyloid imaging,9 together with cerebrospinal fluid (CSF) bio-
markers, as well as functional monitoring of the brain (glucose
metabolism with [18F]FDG or neurotransmitter activity),10,11 are
expected to have a high potential to specifically diagnose AD pa-
tients at a very early stage. During the last 10 years, various mo-
lecular imaging radiolabelled tracers have been reported for the
early diagnosis of AD with single photon emission computed to-
mography (SPECT) and positron emission tomography (PET).12e16
Among them, the thioflavin-T derivative Pittsburgh Compound-
B 1 ([11C]PIB, Fig. 1), a carbon-11 radionuclide marker of A
b pla-
ques,17,18 is currently the most widely used PET tracers in preclinical
and clinical trials for the diagnosis of AD.19e24
* Corresponding author. Tel.: þ33 1 58 80 84 82; fax: þ33 1 40 27 25 84; e-mail
Fig. 1. Chemicals structures of [11C]PIB 1 used for the in vivo imaging of AD and the
precursor 2 used for the radiosynthesis.
address: maite.sylla@cnam.fr (M. Sylla-Iyarreta Veitía).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.085

7346
G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
[
11C]PIB showed high affinity for A
b
aggregates (two binding
radiosynthesis of [11C]PIB or derivatives because of the chemical
functions present on these structures.
sites in AD human brain) and excellent pharmacokinetic profile.25
Interestingly, around 20e30% of asymptomatic controls show
a [11C]PIB retention,26e30 which suggests that this compound might
be an efficient tracer for AD preclinical diagnosis since the major
growth of amyloid burden seems to occur at this stage of the dis-
ease.31,32 This radiopharmaceutical, which is today the gold-
standard amyloid PET tracer,33 is commonly used as a reference
2. Results and discussion
Encouraged by the high interest in the [11C]PIB for Alzheimer’s
disease diagnostic research and considering these previous studies,
we decided to develop a direct synthesis of the precursor 2 of [11C]
to compare the efficiency of new potent markers of
Ab
PIB from two commercially available reagents, by
a Suzu-
aggregates.34
kieMiyaura coupling reaction. The one-step cross-coupling re-
ported herein implies the use of the unprotected 2-bromo-6-
hydroxybenzothiazole 10 and 4-aminophenylboronic acid pinacol
ester 11. Our first attempts with the catalyst Pd2(dba)3 led to the
compound 2 in less than 15% yield, whereas the use of Pd(dppf)
Cl2$CH2Cl2 led to a fast and total conversion of the starting material
(controlled by HPLC) without affecting the hydroxyl and amino
groups (Scheme 2).
Important efforts have been made in the last 5 years to improve
the synthesis of [11C]PIB. The direct N-methylation of the 2-(40-
aminophenyl)-6-hydroxybenzothiazole
2 (Fig. 1) using [
11C]
enriched isotope methylating agent, such as [11C]-methyltriflate
appeared to be the most straightforward method.35,36 Today, this
radiosynthesis can be performed routinely with an automate37
using an HPLC loop to carry out the N-methylation.38
The commonly used method for the synthesis of the precursor 2
of [11C]PIB requires the protection of the phenolic function or the
use of a nitro group as precursor of the amine function. It involves
a five-step synthesis with quite low overall yields ranging from 24
to 39% involving a Jacobson’s oxidative cyclization of substituted
thiobenzanilides.17,39 Few improved syntheses of substituted 2-
arylbenzothiazoles, which could be used as precursors for the
radiosynthesis of [11C]PIB are reported in the literature (Scheme 1).
Kumar et al. described the synthesis of 2-(4-aminophenyl)-6-
methoxybenzothiazole 5 in 35% yield via a SuzukieMiyaura cou-
pling reaction using Pd2(dba)3 in DME/water and aqueous K2CO3.40
Another synthesis, reported by Tamagnan et al. affords the com-
pound 5 through a Heck coupling reaction in 66% yield.41 In the
pyridinyl series, a SuzukieMiyaura coupling reaction, reported by
Svensson et al., leads to the 2-pyridinylbenzothiazole derivative 9
in 61% yield.42 Other methods involving SuzukieMiyaura,43,44
Heck45 or copper-catalyzed46 conditions were reported for the
synthesis of other 2-aryl-6-methoxybenzothiazole derivatives
substituted with mono or dimethylamino functions on the aryl
core, but these compounds cannot be used as precursor for the
The 2-bromo-6-hydroxybenzothiazole 10 and the 4-
aminophenylboronic acid pinacol ester 11 were stirred in a solu-
tion of DMF/2 M K2CO3. After degassing, the Pd(dppf)Cl2$CH2Cl2
was introduced and the reaction mixture was running for 1.5 h at
80 ꢀC. After workup the desired compound 2 was isolated by pre-
cipitation in 94% yield. The compound 2 was isolated clean enough
without additional purification as suggested HPLC and 1H NMR
analysis (Table 1).
These SuzukieMiyaura conditions were successfully extended
to the synthesis of several 2-arylbenzothiazole and 2-
pyridinylbenzothiazole derivatives (Table 1). The hydroxyl and
amino substituents were compatible with the used conditions. The
synthesis of compounds containing nitro substituents (compounds
20, 22, 26 and 30) was also very efficient using the conditions re-
ported. This observation was particularly attractive because nitro
function can be used to introduce fluorine-18, which suggests that
the method developed could lead to efficient syntheses of various
fluorine-18 tracers with chemical structure similar to PIB. The
longer half-life of fluorine-18 (110 min) compared to carbon-11
(20 min) allows for a wider use in clinical settings. Fluorination
Scheme 1. a: Pd2(dba)3$CH2Cl2, K2CO3, DME/water, 100 ꢀC, 6 h. b: Pd(OAc)2, P(t-Bu)3, Cs2CO3, CuBr, DMF, 150 ꢀC, 1 h. c: Pd(dppf)Cl2$CH2Cl2, K2CO3, DMF, 80 ꢀC, 2 h.
Scheme 2. SuzukieMiyaura coupling reaction leading to the precursor 2 of the radiochemical tracer [11C]PIB 1.

G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
7347
Table 1
Biaryl coupling of 2-bromobenzothiazoles (10, 12e15) with various phenyl and pyridinylboronic acid pinacol esters
Entry
1
Aryl halide
Boronic acid pinacol ester
Time (h)
1.5
Product
Yielda (%)
94
HPLC purity (%)
O
10 (OH)
2
92
99
99
NH
B
2
O
O
2
3
10
10
1.5
1.5
19
20
95
70
NH
B
2
O
N
N
N
O
NO
B
2
O
O
NH
B
4
5
10
2
1.5
3
21
5
98
97
99
89
O
NO
2
O
12 (OMe)
NH
B
2
O
O
6
7
12
12
6
9
98
78
96
95
NH
B
2
O
O
1.5
22
NO
B
2
2
O
O
NH
NO
B
8
9
12
2
23
24
99
99
95
87
O
2
O
13 (Me)
1.5
NH
B
2
O
O
10
11
12
13
13
13
12
5
25
26
27
82
64
97
93
99
92
NH
B
2
O
O
NO
B
2
O
O
NH
B
2
1
O
NO
2
O
13
14
14 (NO2)
2
2
28
29
74
64
NH
B
2
O
O
14
13b
62
NH
B
2
(continued on next page)
O
N

7348
G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
Table 1 (continued )
Entry
Aryl halide
Boronic acid pinacol ester
Time (h)
1
Product
Yielda (%)
60b
HPLC purity (%)
99
O
15
16
14
30
NO
B
2
O
O
NH
B
14
2
1
31
32
78
70
87
95
O
NO
2
O
NH
17
15 (NH2)
B
4
2
O
a
Yields refer to isolated products.
Isolated yields after column chromatography.
b
by nucleophilic substitution of the nitro group was reported for the
radiopharmaceuticals 2-(4-[18F]fluorophenyl)-6-methoxybenzoth-
iazole and 2-(4-[18F]fluoro phenyl)-6-methylbenzothiazole, which
showed high potential for PET amyloid imaging.47 The precursors of
these two radiopharmaceuticals were successfully synthesized
here using the SuzukieMiyaura approach proposed (compounds 22
and 26).
The SuzukieMiyaura method described here offers a fast and
easy access to key intermediates used in the synthesis of radio-
pharmaceuticals with chemical structures close to the PIB. Taking
advantage of the presence of the amino or nitro substituent in the
structure, some of them could directly be labelled.
Microwave-assisted heating under controlled conditions has
gained importance in organic chemistry due to homogenous and
short time heating and energy saving. Considering the results ob-
tained under thermal conditions, the Suzuki cross-coupling re-
actions were undertaken under controlled microwave activation.
Several examples of SuzukieMiyaura reactions performed upon
microwave activation for the synthesis of various heterocyclic
scaffolds of pharmacological interest have been described in the
literature.48
The microwave conditions for the synthesis of each series of
arylbenzothiazoles were optimized. A preliminary study was
developed using different conditions of temperature and activa-
tion power. The catalytic system (5 mol % of Pd(dppf)Cl2$CH2Cl2)
used for reactions under conventional heating was compatible
with microwave conditions and rapid couplings were observed
within 5 min at 60 ꢀC and total conversion was obtained after
15 min.
The use of microwave activations resulted in a dramatic de-
crease of reaction times. When 2-bromo-6-hydroxybenzothiazole
was used as reagent, this synthesis proved to be efficient with an
irradiation of 10 W for 15 min at 60 ꢀC. The best results were ob-
tained for compounds 2 and 19 isolated in 93% and 92% yields,
respectively, with an HPLC purity higher than 92%. Moreover
microwave-assisted SuzukieMiyaura reaction was found to be
compatible with other series of 2-bromobenzothiazoles bearing
methoxy and methyl groups. The reaction of aryl halide 12 and 13
with phenylboronic acid pinacol esters 11, 16e18, required an ir-
radiation of 50 W for 15 min at 60 ꢀC for total conversion. The best
results were obtained for compounds 5 and 22 with 98% and 96%
yields, respectively (Table 2).
Table 2
Biaryl coupling of 2-bromobenzothiazole (10, 12, 13) with various phenylboronic acid pinacol esters performed by microwave activation
Entry
1
Aryl halide
Boronic acid pinacol ester
Conditions
Product
Yielda (%)
93
HPLC purity (%)
94
O
10 (OH)
10 W, 60 ꢀC, 15 min
2
NH
B
2
O
O
2
3
4
10
10
10
10 W, 60 ꢀC, 15 min
10 W, 60 ꢀC, 15 min
10 W, 60 ꢀC, 15 min
19
20
21
92
87
85
99
96
96
NH
B
2
O
N
O
NO
B
2
O
O
NH2
NO2
B
O

G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
7349
Table 2 (continued )
Entry
Aryl halide
Boronic acid pinacol ester
Conditions
Product
Yielda (%)
98
HPLC purity (%)
O
5
6
7
12 (OMe)
50 W, 60 ꢀC, 15 min
5
77
88
NH
B
2
O
O
12
50 W, 150 ꢀC, 15 min
9
68
NH
B
2
O
N
O
12
50 W, 60 ꢀC, 15 min
50 W, 80 ꢀC, 15 min
22
24
96
84
91
81
NO
B
2
O
O
8
13 (Me)
NH
B
2
O
a
Yields refer to isolated products.
The high yields (68e98%) and short reaction times provided by
the microwave-assisted SuzukieMiyaura cross-coupling described
here are decisive advantages. As expected, the unprotected phenol
and amine functions are well tolerated by these coupling condi-
tions, which makes this synthesis a very straightforward route to
get the precursor of the [11C]PIB and other derivatives. An exten-
sion of this method towards the synthesis of other functionalized
arylbenzothiazoles is currently under study.
4.2. Physical measurements
The structure of the products prepared by different methods
was checked by comparison of their NMR, IR and MS data and by
the TLC behaviour. 1H and 13C NMR spectra were acquired on
a Bruker BioSpin GmbH spectrometer 400 MHz, at room temper-
ature. Chemical shifts are reported in
d units, parts per million
(ppm). Coupling constants (J) are measured in hertz (Hz). Splitting
patterns are designed as follows: s, singlet; d, doublet; dd, doublet
of doublets, m, multiplet; br, broad. Various 2D techniques and
DEPT experiments were used to establish the structures and to
assign the signals. For the assignments of the NMR signals, we use
the convention presented in Fig. 2. GCeMS analyses were per-
formed with an Agilent 6890N instrument equipped with
a 12 mꢁ0.20 mm dimethyl polysiloxane capillary column and an
Agilent 5973N MS detector-column temperature gradient
100e300 ꢀC (method 100): 100 ꢀC (1 min); 100 ꢀCe220 ꢀC (10 ꢀC/
min); 200 ꢀC (2 min); gradient 160e280 ꢀC (method 160): 160 ꢀC
(1 min); 160 ꢀCe280 ꢀC (10 ꢀC/min); 280 ꢀC (2 min); gradient
180e300 ꢀC (method 180): 180 ꢀC (1 min); 180 ꢀCe300 ꢀC (10 ꢀC/
min); 300 ꢀC (2 min); gradient 220e325 ꢀC (method 220): 220 ꢀC
(1 min); 220 ꢀCe325 ꢀC (10 ꢀC/min); 325 ꢀC (7.5 min), gradient
260e325 ꢀC (method 260): 260 ꢀC (1 min); 260 ꢀCe325 ꢀC (10 ꢀC/
min); 325 ꢀC (7.5 min), low-resolution mass spectra (LRMS)
resulting from ionization by electronic impact. Infrared spectra
were recorded over the 400e4000 cmꢂ1 range with an Agilent
Technologies Cary 630 FTIR/ATR/ZnSe spectrometer. Low-
resolution mass spectra (LRMS) were also performed from ioniza-
tion by electrospray (ESIeLRMS) on a Waters Micromass ZQ2000
(mass) spectrometer. The mass analyses of compounds were made
by direct introduction carried out by infusion over 2 min of the
sample dissolved in methanol/HCO2H 0.1% (1 mg/mL) within a flow
3. Conclusions
We have developed an efficient and rapid synthesis of the pre-
cursor of the widely used radionuclide [11C]PIB, a PET tracer
employed for the in vivo imaging of AD. This method was efficiently
applied in the synthesis of various 2-arylbenzothiazole derivatives
containing key functions for radiolabelling with carbon-11 (amino
group) or fluorine-18 (nitro group). The SuzukieMiyaura cross-
coupling reaction can be performed from commercially available
reactants to achieve the simple one-step synthesis of radiophar-
maceutical precursors in high yields under conventional and mi-
crowave heating.
4. Experimental section
4.1. Chemicals
All reagents were obtained from commercial sources unless
otherwise noted, and used as received. Heated experiments were
conducted using thermostatically controlled oil baths and were
performed under an atmosphere oxygen-free in oven-dried
glassware. All reactions were monitored by analytical thin layer
chromatography (TLC) or by Gas chromatographyeMass spec-
trometry (GCeMS). TLC was performed on aluminium sheets
precoated silica gel plates (60F254, Merck). TLC plates were visu-
alized using irradiation with light at 254 nm, ninhydrin sprays or
in an iodine chamber as appropriate. Frontal retention values Rf
have been mentioned when necessary. Flash column chromatog-
raphy was carried out when necessary using silica gel 60 (particle
size 0.040e0.063 mm, Merck). The reactions using microwaves as
the activating/heating source were accomplished using a micro-
wave oven (CEM Discover 1Ô) under pressure and was monitored
by ChemDriver.
rate of 30 mL/min. The abundance indicated for each mass number
(m/z values) is given in percentage relative to the strongest peak of
100% abundance (base peak).
7
1
3'
2'
6
8
9
R
S
1'
2
4'
Y
5
N
3
X
5'
4
6'
Fig. 2. Convention adopted to assign signals of 1H and 13C NMR spectra.

7350
G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
0
High-resolution mass spectra (HRMS) analyses were acquired
on a Thermo Scientific LTQ Orbitrap mass spectrometer. The HPLC
analyses were carried out on a normal phase column Kromasil
J¼8.8 Hz, H2 ), 7.41 (d, 1H, J7-5¼2.7 Hz, H7), 7.05 (sbroad, 1H, NH2);
0
0
7.00 (dd, 1H, J5-7¼2.5 Hz, J5-4¼8.5 Hz, H5), 6.71 (d, 1H, J3 -2 ¼8.9 Hz,
H3 ), 13C NMR (DMSO-d6, 100 MHz):
d
¼161.1 (C2), 159.5 (C6), 155.4
0
0
0
0
(length: 250 mm, diameter: 4.6 mm, stationary phase: 5
mm) using
(C4 ), 146.9 (C9), 143.9 (C6 ), 136.7 (C2 ), 135.1 (C8), 122.7 (C4), 118.2
0
0
a Water 2998 Photodiode Array Detector (260e370 nm) and an
isocratic system of elution. The retention times tR are expressed in
minutes in the decimal system.
(C1 ), 115.8 (C5), 109.6 (C3 ), 106.8 (C7). HPLC purity: 99%, Krom Si
250, AcOEt 100%, 0.8 mL minꢂ1
,
l¼338 nm, tR¼11.4 min. GC/MS:
method 180 (1 min); tR¼8.97 min m/z: 243 [M]þ(100), 242
Chemical nomenclature of labelled compounds: [18F]FDG, 2-
[MꢂH]þ(100), 227 [MꢂOH]þ(5); IR (ATR):
n 3330 (nNH2), 1630,
[
18F]-fluoro-2-deoxy-
D
-glucose; [11C]PIB, Pittsburgh Compound-B
1561, 1451 (nC]C), 1250 (nCeN), 825 (dCeH). HRMS: calcd for
or [N-[11C]methyl]2-(40-methylaminophenyl)-6-hydroxy benzo-
C
12H9N3OSH [MþH]þ (244.05391); found (244.05396).
thiazole;
[
125I]IMPY, 6-[125I]iodo-2-(40-dimethylamino)phenyl-
imidazo[1,2]pyridine.
4.3.3. 2-(40-Nitrophenyl)-6-hydroxybenzothiazole (20). 2-Bromo-6-
hydroxybenzothiazole 10 (150.7 mg, 0.66 mmol) and 4-
nitrophenylboronic acid pinacol ester 17 (196.8 mg, 0.79 mmol)
were dissolved in 3.3 mL of DMF in the presence of 2 mL of 2 M K2CO3
(4 mmol, 6.0 equiv). After 1 h under argon bubbling, Pd(dppf)
Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the reaction
was performed at 80 ꢀC for 1.5 h (monitoring by TLC, cyclohexane/
EtOAc 1:1). Afterworkup 2-(40-nitrophenyl)-6-hydroxybenzothiazole
20 was isolated by filtration as a yellow amorphous powder. Yield
126 mg (70%). Rf¼0.5, SiO2 (cyclohexane/EtOAc 1:1); 1H NMR (DMSO-
4.3. General procedure for the preparation of benzothiazole
derivatives by SuzukieMiyaura coupling reaction
The corresponding 2-bromobenzothiazoles 10, 12e15
(0.66 mmol, 1 equiv) and the corresponding phenylboronic acid
pinacol ester (0.79 mmol, 1.2 equiv) were dissolved in anhydrous
DMF in the presence of K2CO3 (6.0 equiv). After 1 h under argon
bubbling, Pd(dppf)Cl2$CH2Cl2 (0.033 mmol, 0.05 equiv) was in-
troduced and the mixture was stirred at 80 ꢀC or under microwave
irradiation (monitoring by TLC or by GCeMS). Later, the mixture
was then filtered on CeliteÒ, concentrated and dissolved in 4 mL of
1 N MeOH/HCl. Then 75 mL of Et2O were introduced and a colour
powder was isolated by filtration. The precipitate was poured into
water and pH adjusted to 6. The expected compounds were isolated
by filtration and purity was checked by HPLC.
0
0
0
0
d6, 400 MHz)
d
¼10.21 (sbroad,1H, OH), 8.40 (d, 2H, J3 -2 or J5 -6 ¼8.9 Hz,
0
0
0
0
0
0
0
0
H3 and H5 ), 8.8 (d, 2H, J2 -3 or J6 -5 ¼8.8 Hz, H2 and H6 ), 8.97 (d,1H, J4-
¼8.8 Hz, H4), 7.52 (d,1H, J7-5¼2.4 Hz, H7), 7.10 (dd,1H, J5-7¼2.4 Hz, J5-
5
¼8.9 Hz, H5), 13C NMR (DMSO-d6,100 MHz):
¼160.8 (C2),156.5 (C6),
d
4
0
0
0
0
148.2 (C4 ), 147.15 (C9), 138.7 (C1 ), 136.8.1 (C8), 128.6 (C2 and C6 ),
124.5.7 (C4 and C5), 106.8 (C7). HPLC purity: 99%, Krom Si 250, Hep-
tane/AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼338 nm, tR¼6.06 min. GC/MS:
method 180; tR¼9.24 min m/z: 272 [M]þ(100), 242 [MꢂNO]þ(25), 226
4.3.1. 2-(40-Aminophenyl)-6-hydroxybenzothiazole (2). 2-Bromo-6-
hydroxybenzothiazole 10 was purchased from Bellenchem com-
mercial source. 2-Bromo-6-hydroxybenzothiazole 10 (150.7 mg,
0.66 mmol) and 4-aminophenylboronic acid pinacol ester 11
(173.5 mg, 0.79 mmol) were dissolved in 3.3 mL of DMF in the
presence of 2 mL of 2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under
argon bubbling, Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was
introduced and the reaction was performed at 80 ꢀC for 1.5 h
(monitoring by TLC, cyclohexane/EtOAc 1:1). After workup 2-(40-
aminophenyl)-6-hydroxybenzothiazole 2 was isolated by filtration
as a grey amorphous powder. Yield 151 mg (94%). Rf¼0.2, SiO2 (cy-
[MꢂNO2]þ(55). IR (ATR):
n 3431e3083 (nOH), 1657 (nC]C), 1513
(
nasNO2), 1338 (nsNO2), 849 (dCH). HRMS: calcd for C13H8N2O3SH
[MþH]þ (273.03284); found (273.03278).
4.3.4. 2-(40-Amino-3-nitrophenyl)-6-hydroxybenzothiazole (21). 2-
Bromo-6-hydroxybenzothiazole 10 (150.7 mg, 0.66 mmol) and 4-
amino-3-nitrophenylboronic acid pinacol ester 18 (208.6 mg,
0.79 mmol) were dissolved in 3.3 mL of DMF in the presence of
2 mL of 2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon
bubbling, Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was in-
troduced and the reaction was performed at 80 ꢀC for 1.5 h (mon-
itoring by TLC, cyclohexane/EtOAc 4:6). After workup 2-(40-amino-
3-nitrophenyl)-6-hydroxybenzothiazole 21 was isolated by filtra-
tion as a brown amorphous powder. Yield 185 mg (98%). Rf¼0.4,
SiO2 (cyclohexane/EtOAc 4:6); 1H NMR (DMSO-d6, 400 MHz)
clohexane/EtOAc 1:1). 1H NMR (DMSO-d6, 400 MHz)
d
0
9.79 (s, 1H,
0
0
0
0
OH), 7.73 (d,1H, J4-5¼8.7 Hz, H4), 7.70 (d, 2H, J2 -3 or J6 -5 ¼8.2 Hz, H2
0
and H6 ), 7.36 (d, 1H, J7-5¼2.6 Hz, H7), 6.95 (dd, 1H, J5-7¼2.4 Hz, J5-
0
0
0
0
0
0
¼8.7 Hz, H5), 6.68 (d, 2H, J3 -2 or J5 -6 ¼8.4 Hz, H3 and H5 ), 5.83 (s,
4
1H, NH2), (similar to literature49); 13C NMR (DMSO-d6, 100 MHz):
d
¼9.98 (sbroad, 1H, OH), 8.56 (d, 1H, H6 , J6 -2¼2.4 Hz), 8.03 (dd, 1H,
0
0
0
0
0
0
0
0
d
¼164.6 (C2), 154.9 (C6), 151.5 (C4 ), 147.4 (C9), 135.1 (C8), 128.2 (C2
J2 -3¼9.04 Hz, J2 -6 ¼2.3 Hz, H2 ), 7.97 (sbroad, 1H, NH2); 7.83 (d,1H, J4-
0
0
0
0
0
0
and C6 ), 122.3 (C4), 120.6 (C1 ), 115.4 (C5), 113.6 (C3 and C5 ), 106.7
¼8.8 Hz, H4), 7.44 (d, 1H, J7-5¼2.2 Hz, H7), 7.21 (d, 1H, J3 -2 ¼8.9 Hz,
5
(C7). m/z (ESIþ): 243 (100%, [MþH]þ). HPLC purity: 92%, Krom Si
H3 ), 7.01 (dd, 1H, J5-7¼2.2 Hz, J5-4¼8.6 Hz, H5), 13C NMR (DMSO-d6,
0
250, Heptane/AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼338 nm, tR¼12.3 min.
100 MHz):
d
¼161.9 (C2), 155.5 (C6), 147.4 (C9), 146.9 (C4 ), 135.4 (C8),
0
GC/MS: method 180, tR¼9.01 min; m/z: 242 [M]þ(100), 226
133.3 (C2 ), 129.9 (C5 ), 123.7 (C6 ), 122.9 (C4), 120.6 (C1 ), 120.2 (C3),
115.9 (C5), 106.8 (C7). HPLC purity: 99%, Krom Si 250, Heptane/
0
0
0
0
[MꢂNH2]þ (0.1), IR (ATR):
n 3330 (nNH2), 1601, 1570, 1483, 1454
(n
C]C), 832 (
d
CeH). HRMS: calcd for C13H10N2OSH [MþH]þ
AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼338 nm, tR¼10.65 min. GC/MS:
(243.05866); found (243.05864).
method 220; tR¼8.00 min, m/z: 287 [M]þ(100), 257 [MꢂNO]þ(10),
241 [MꢂNO2]þ(53). IR (ATR):
n 3464e3197 (nOH), 3344 (nNH2),
4.3.2. 2-(60-Aminopyridin-3-yl)-6-hydroxybenzothiazole
(19). 2-
1633, 1564 (nC]C), 1344 (nsNO2), 819 (d CeH). HRMS: calcd for
Bromo-6-hydroxybenzothiazole 10 (150.7 mg, 0.66 mmol) and 2-
aminopyridine-5-boronic acid pinacol ester 97% 16 (179.7 mg,
0.79 mmol) were dissolved in 7 mL of DMF in the presence of 2 mL
of 2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 1.5 h (monitoring by TLC, cy-
clohexane/EtOAc 1:1). After workup 2-(60-aminopyridin-3-yl)-6-
hydroxybenzothiazole 19 was isolated by filtration as a green
amorphous powder. Yield 152 mg (95%). Rf¼0.1, SiO2 (cyclohexane/
C
13H9N3O3SNa [MþNa]þ (310.02568); found (310.02580).
4.3.5. 2-(40-Aminophenyl)-6-methoxybenzothiazole (5). 2-Bromo-
6-methoxybenzothiazole 12 (167.8 mg, 0.66 mmol) previously
synthesized from 2-amino-6-methoxybenzothiazole and 4-
aminophenylboronic acid pinacol ester 11 (173.5 mg, 0.79 mmol)
weredissolved in 3.3 mL of DMF in the presence of 2 mL of 2 M K2CO3
(4 mmol, 6.0 equiv). After 1 h under argon bubbling, Pd(dppf)
Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the reaction
was performed at 80 ꢀC for 3 h (monitoring by TLC, cyclohexane/
EtOAc 1:1). After workup 2-(40-aminophenyl)-6-methoxybenzo-
EtOAc 1:1); 1H NMR (DMSO-d6, 400 MHz)
d
¼9.84 (s, 1H, OH), 8.58
0
(s, 1H, H6 ), 7.97 (dd, 1H, J4-5¼8.8 Hz, J4-7¼2.4 Hz, H4), 7.77 (d, 1H,

G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
7351
thiazole 5 was isolated by filtration as a brown amorphous powder.
Yield 164.3 mg (97%). Rf¼0.4, SiO2 (cyclohexane/EtOAc 1:1); Mp
After workup 2-(40-amino-3-nitrophenyl)-6-methoxybenzothi-
azole 23 was isolated by filtration as a brown amorphous powder.
97e99 ꢀC, 1H NMR (DMSO-d6, 400 MHz)
d¼7.85 (d, 1H, J4-5¼8.9 Hz,
Yield 211 mg (99%).1H NMR (DMSO-d6, 400 MHz)
d
¼8.53 (s,1H, H6 ),
0
0
0
0
0
0
0
0
0
H4), 7.81 (d, 2H, J2 -3
J6 -5 ¼8.5 Hz, H2 and H6 ), 7.65 (d, 1H, J7-
7.99 (d,1H, J2 -3¼8.4 Hz, H2 ), 7.86 (d,1H, J4-5¼8.1 Hz, H4), 7.64 (s,1H,
or
H7), 7.19 (d, 1H, J3 -2 ¼8.5 Hz, H3 ), 7.09 (d, 1H, J5-4¼8.3 Hz, H5). 13
C
0
0
0
¼2.5 Hz, H7), 7.10 (dd, 1H, J5-7¼2.5 Hz, J5-4¼9.0 Hz, H5), 6.84 (d, 2H,
5
J3 -2 or J5 -6 ¼8.7 Hz, H3 and H5 ), 3.84 (s, 3H, CH3); 13C NMR (DMSO-
NMR (DMSO-d6, 100 MHz):
d
¼163.1 (C2), 157.2 (C6), 147.7 (C9), 147.5
0
0
0
0
0
0
0
0
0
0
0
d6, 100 MHz):
d
¼165.4 (C2), 164.6 (C4 ), 149.4 (C6), 148.1 (C9), 135.2
(C4 ), 138.4 (C8), 133.2 (C2 ), 129.8 (C5 ), 123.8 (C6 ), 122.8 (C4), 120.3
0
0
0
0
0
(C8),128.3 (C2 and C6 ),122.4 (C4),121.9 (C1 ),115.2 (C5),115.0 (C3 and
(C1 ), 120.2 (C3), 115.7 (C5), 104.8 (C7), 55.7 (CH3). HPLC purity: 95%,
5 ), 104.9 (C7), 55.7 (CH3). HPLC purity: 89%, Krom Si 250, Heptane/
Krom Si 250, Heptane/AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼338 nm,
0
AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼338 nm, tR¼9.57 min. GC/MS: method
tR¼8.59 min. GC/MS: method 160; tR¼13.71 min, m/z: 301 [M]þ
160; tR¼10.80 min, m/z: 256 [M]þ(86), 241 [MꢂCH3]þ(100), IR (ATR):
(100), 286 [MꢂCH3]þ (43), 255 [MꢂNO2]þ(20). IR (ATR):
n 3457
n
3427e3500 (
n
NH2), 2835 (
n
OCH3), 1603, 1463, 1433 (
nC]C), 831
(
n
NH2), 2834 (
nOCH3), 1628, 1561 (nC]C), 1512 (nasNO2), 1252
(d
CeH). HRMS: calcd for C14H12N2OSH [MþH]þ (257.07431); found
(nsNO2), 818 (
d
CeH). HRMS: calcd for C14H11N3O3SNa [MþNa]þ
(257.07462).
(324.04133); found (324.04135).
4.3.6. 2-(60-Aminopyridin-3-yl)-6-methoxybenzothiazole
(9). 2-
4.3.9. 2-(40-Aminophenyl)-6-methylbenzothiazole (24). 2-Bromo-6-
methylbenzothiazole 13 previously synthesized from 2-amino-6-
methylbenzothiazole (150.5 mg, 0.66 mmol) and 4-
aminophenylboronic acid pinacol ester 11 (173.5 mg, 0.79 mmol)
were dissolved in 3.3 mL of DMF in the presence of 2 mL of 2 M
K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 1.5 h (monitoring by TLC, cy-
clohexane/EtOAc 1:1). After workup 2-(40-aminophenyl)-6-
methylbenzothiazole 24 was isolated by filtration as a yellow-
brown amorphous powder. Yield 156.9 mg (99%). Rf¼0.4,
Bromo-6-methoxybenzothiazole 12 (167.8 mg, 0.66 mmol) and 2-
aminopyridine-5-boronic acid pinacol ester 97% 16 (179.7 mg,
0.79 mmol) were dissolved in 7 mL of DMF in the presence of 2 mL of
2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 6 h (monitoring by GCeMS).
After workup 2-(60-aminopyridin-3-yl)-6-methoxybenzothiazole 9
was isolated by filtration as a brown amorphous powder. Yield
0
171.4mg (98%).1HNMR (DMSO-d6, 400 MHz)
d
¼8.63 (s,1H, H6 ), 7.99
0
0
0
(d,1H, J2 -3 ¼8.7 Hz, H2 ), 7.99 (d,1H, J4-5¼8.6 Hz, H4), 7.67 (s,1H, H7),
7.10 (dd,1H, J5-7¼2.3 Hz, J5-4¼8.7 Hz, H5), 6.73 (sbroad,1H, NH2); 6.62
SiO2 (cyclohexane/EtOAc 1:1). 1H NMR (DMSO-d6, 400 MHz)
d¼7.82
(d,1H, J3 -2 ¼8.6 Hz H3 ).13C NMR (DMSO-d6,100 MHz):
d¼163.3 (C2),
(d, 1H, H7), 7.81 (d, 1H, J4-5¼8.6 Hz, H4), 7.76 (d, 2H, J2 -3
0
0
0
0
0
0
J6 -
or
0
0
0
0
0
0
161.3 (C6), 156.9 (C4 ), 147.9 (C9), 147.3 (C6 ), 135.4 (C2 ), 134.9 (C8),
¼8.4 Hz, H2 and H6 ), 7.29 (dd, 1H, J5-7¼1.6 Hz, J5-4¼8.1 Hz, H5),
5
0
0
0
0
0
0
0
0
122.4 (C4), 117.8 (C1 ), 115.3 (C5), 108.1 (C3 ), 104.9 (C7), 55.7 (CH3).
6.70 (d, 2H, J3 -2
NMR (DMSO-d6, 100 MHz):
(C8), 133.8 (C6), 128.5 (C2 and C6 ), 127.5 (C5), 121.5 (C7), 121.3 (C4),
J5 -6 ¼8.4 Hz H3 and H5 ), 2.45 (s, 3H, CH3). 13C
or
HPLCpurity: 96%, Krom Si 250, AcOEt100%, 0.8mL minꢂ1
,
l
¼338nm,
d
¼167 (C2), 151.9 (C9), 151.8 (C4 ), 133.9
0
0
0
tR¼10.8 min. GC/MS: method 160; tR¼10.65 min, m/z: 257
[M]þ(100), 242 [MꢂCH3]þ(95). IR (ATR):
n
3428 (
CeH). HRMS: calcd for
n
NH2), 2834 (
n
120.2 (C1 ), 113.6 (C3 and C5 ), 55.7 (CH3). HPLC purity: 87%, Krom Si
0
0
0
OCH3), 1652, 1600, 1460, 1435 (
n
C]C), 813 (
d
250, Heptane/AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼338 nm, tR¼8.08 min.
C
13H11N3OSH [MþH]þ (258.06956); found (258.06989).
GC/MS: method 100; tR¼15.6 min, m/z: 240[M]þ (100), 224
[MꢂNH2]þ (0.5). IR (ATR):
n 3464 (nNH2), 1631, 1605, 1477, 1454
4.3.7. 2-(40-Nitrophenyl)-6-methoxybenzothiazole (22). 2-Bromo-
6-methoxybenzothiazole 12 (106 mg, 0.43 mmol) and 4-
nitrophenylboronic acid pinacol ester 17 (136 mg, 0.56 mmol)
were dissolved in 4 mL of DMF in the presence of 1.3 mL of 2 M
K2CO3 (2.6 mmol, 6.0 equiv). After 30 min under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 2 h (monitoring by GCeMS).
After workup 2-(40-nitrophenyl)-6-methoxybenzothiazole 22 was
isolated by filtration as a yellow amorphous powder. Yield 96 mg
(n
C]C), 813
(d
CeH). HRMS: calcd for C14H12N2SH [MþH]þ
(241.07940); found (241.07942).
4.3.10. 2-(60-Aminopyridin-3-yl)-6-methylbenzothiazole
(25). 2-
Bromo-6-methylbenzothiazole 13 (150.5 mg, 0.66 mmol) and 2-
aminopyridine-5-boronic acid pinacol ester 97% 16 (179.7 mg,
0.79 mmol) were dissolved in 7 mL of DMF in the presence of 2 mL of
2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 12 h (monitoring by GCeMS).
After workup 2-(60-aminopyridin-3-yl)-6-methylbenzothiazole 25
was isolated by filtration as a grey amorphous powder. Yield
130.8 mg (82%). Rf¼0.3, SiO2 (cyclohexane/EtOAc 1:1). 1H NMR
(78%). 1H NMR (DMSO-d6, 400 MHz)
d
¼8.38 (d, 2H, J3 -2
J5 -
0
0
0
or
0
0
0
0
0
0
0
0
0
¼8.5 Hz, H3 and H5 ), 8.3 (d, 2H, J2 -3 or J6 -5 ¼8.5 Hz, H2 and H6 ),
6
8.03 (d, 1H, J4-5¼8.9 Hz, H4), 7.8 (d, 1H, J7-5¼2.6 Hz, H7), 7.20 (dd, 1H,
J5-7¼2.6 Hz, J5-4¼8.9 Hz, H5), 3.88 ppm (s, 3H, CH3) (similar to
literature).48 13C NMR (DMSO-d6, 100 MHz):
d¼162.1 (C2), 158.2
(DMSO-d6, 400 MHz) d
¼8.63 (d,1H, J6 -2¼2.5 Hz, H6 ), 8.02 (dd,1H, J2 -
0
0
0
0
0
0
0
0
0
(C6), 148.3 (C4 ), 138.8 (C9), 136.8 (C8), 135.6 (C2 ), 127.8 (C4), 126.2
¼8.6 Hz, J2 -6 ¼2.5 Hz, H2 ), 7.85 (s,1H, H7), 7.84 (d,1H, J4-5¼8.04 Hz,
3
0
0
0
(C6 ), 124.5 (C1 ), 124.1 (C3 ), 115.7 (C5), 104.8 (C7), 55.9 (CH3). HPLC
H4), 7.32 (dd, 1H, J5-7¼1.5 Hz, J5-4¼8.9 Hz, H5), 6.79 (sbroad, 1H, NH2),
purity: 95%, Krom Si 250, Heptane/AcOEt 50:50, 0.8 mL minꢂ1
,
6.61 (d, 1H, J3 -2 ¼8.6 Hz, H3 ), 2.47 (s, 3H, CH3). 13C NMR (DMSO-d6,
0
0
0
¼362 nm, tR m/z (ESIþ): 287 (100%, [MþH]þ). GC/MS: method 100;
100 MHz): d
¼167.4 (C4 ), 164.7 (C2), 161.3 (C9), 151.7 (C6 ), 135.6 (C2 ),
0
0
0
l
tR¼16.83 min m/z: 286 [M]þ (100), 271 [MꢂCH3]þ (25), 240
134.3 (C8),133.7 (C6),127.7(C5),121.6and 121.5 (C4 and C7),117.6 (C1 ),
0
[MꢂNO2]þ (20). IR (ATR):
n
3081 (
n
C]C), 2838 (
nOCH3), 1591, 1551
108.0 (C3 ), 20.9 (CH3). HPLC purity: 93%, Krom Si 250, AcOEt 100%,
0
(n
C]C), 1514 (nasNO2), 1313 (nsNO2), 846 (
dCeH). HRMS: calcd for
0.8 mL minꢂ1
,
l
¼338 nm, tR¼10.02 min. GC/MS: method 100;
C
14H10N2O3SH [MþH]þ (287.04851); found (287.04849).
tR¼15.45 min, m/z: 241 [M]þ (100), 225 [MꢂNH2]þ (6). IR (ATR):
n
3385 (nNH2), 1607, 1454 (nC]C), 1396 (nCeN), 808 (dCeH). HRMS:
4.3.8. 2-(40-Amino-3-nitrophenyl)-6-methoxybenzothiazole (23). 2-
Bromo-6-methoxybenzothiazole 12 (106 mg, 0.43 mmol) and 4-
amino-3-nitrophenylboronic acid pinacol ester 18 (208.6 mg,
0.79 mmol) were dissolved in 4.3 mL of DMF in the presence of 2 mL
of 2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 2 h (monitoring by GCeMS).
calcd for C13H11N3SH [MþH]þ (242.07464); found (242.07465).
4.3.11. 2-(40-Nitrophenyl)-6-methylbenzothiazole (26). 2-Bromo-6-
methylbenzothiazole 13 (150.5 mg, 0.66 mmol) and 4-
nitrophenylboronic acid pinacol ester 17 (196.8 mg, 0.79 mmol)
were dissolved in 7 mL of DMF in the presence of 2 mL of 2 M K2CO3
(4 mmol, 6.0 equiv). After 1 h under argon bubbling, Pd(dppf)

7352
G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the reaction
was performed at 80 ꢀC for 5 h (monitoring by GCeMS). After
workup 2-(40-nitrophenyl)-6-methylbenzothiazole 26 was isolated
by filtration as a yellow amorphous powder. Yield 114.2 mg (64%).
0.79 mmol) were dissolved in 7 mL of DMF in the presence of 2 mL of
2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 2 h (monitoring by TLC, cyclo-
hexane/EtOAc 1:1). After workup 2-(60-aminopyridin-3-yl)-6-
nitrobenzothiazole 29 was isolated by filtration as a beige solid.
The crude was purified by flash chromatography on silica gel to af-
ford the expected compound 29 as yellow oil. Yield 24 mg (13%).
Rf¼0.3, SiO2 (cyclohexane/EtOAc 1:1); 1H NMR (DMSO-d6, 400 MHz)
1H NMR (DMSO-d6, 400 MHz)
d
¼8.42 (d, 2H, J3 -2
J5 -6 ¼8.8 Hz,
0
0
0
0
or
0
0
0
0
0
0
0
0
H3 and H5 ), 8.38 (d, 2H, J2 -3 or J6 -5 ¼9 Hz, H2 and H6 ), 8.06 (d, 1H,
J4-5¼8.3 Hz, H4), 8.05 (s, 1H, H7), 7.46 (dd, 1H, J5-7¼1.8 Hz, J5-
¼8.2 Hz, H5), 1.36 ppm (s, 3H, CH3). 13C NMR (DMSO-d6, 100 MHz):
4
d
0
0
¼163.6 (C2), 151.7 (C9), 148.5 (C4 ), 138.4 (C1 ), 136.4 (C8), 135.2 (C6),
0
0
0
0
124.7 (C5), 128.2 (C2 and C6 ), 124.6 (C3 and C5 ), 122.6 and 122.1 (C4
and C7), 24.6 (CH3). HPLC purity: 99%, Krom Si 250, Heptane/AcOEt
d
¼9.09 (s, 1H, H7), 8.30 (d, 1H, J5-4¼9.1 Hz, H5), 8.02 (d, 2H, J4-
0
0
0
0
0
0
¼9.1 Hz, H4), 7.85 (d, 2H, J2 -3 or J6 -5 ¼8.3 Hz, H2 and H6 ), 7.72 (d,1H,
5
50:50, 0.8 mL minꢂ1
,
l
¼345 nm, tR¼4.44 min. GC/MS: method 100,
J3 -2 or J5 -6 ¼8.4 Hz, H3), 6.22 (s,1H, NH2); HPLC purity: 62%, Krom Si
0
0
0
0
tR¼15.61 min, m/z: 270 [M]þ (100), 224 [MꢂNO2]þ (45), 209
250, AcOEt 100%, 0.8 mL minꢂ1
,
l¼362 nm, tR¼8.11 min. IR (ATR):
n
[224ꢂCH3]þ (30), IR (ATR):
n
3079 (
n
]CeH), 1515 (nasNO2), 1338
3422 (nNH2), 1656 (nC]C), 823 (dCeH). HRMS: calcd for
(
nsNO2), 849 (
d
CeH). HRMS: calcd for C14H10N2O2SH [MþH]þ
C
12H9N3OSH [MþH]þ (272.03681); found (273.03685).
(271.05357); found (271.05403).
4.3.15. 2-(40-Nitrophenyl)-6-nitrobenzothiazole (30). 2-Bromo-6-
nitrobenzothiazole 14 (170.9 mg, 0.66 mmol) and 4-
nitrophenylboronic acid pinacol ester 17 (196.8 mg, 0.79 mmol)
were dissolved in 3.3 mL of DMF in the presence of 2 mL of 2 M
K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon bubbling,
Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the
reaction was performed at 80 ꢀC for 1 h (monitoring by TLC, cy-
clohexane/EtOAc 1:1). After workup 2-(40-nitrophenyl)-6-
nitrobenzothiazole 30 was isolated by filtration as an amorphous
solid. The crude was purified by flash chromatography on silica gel
(cyclohexane/EtOAc 1:1) to afford the expected compound 30 as
yellow amorphous powder. Yield 119 mg (60%). Rf¼0.3,
SiO2 (cyclohexane/EtOAc 1:1); 1H NMR (DMSO-d6, 400 MHz)
4.3.12. 2-(40-Amino-3-nitrophenyl)-6-methylbenzothiazole (27). 2-
Bromo-6-methylbenzothiazole 13 (150.5 mg, 0.66 mmol) and 4-
amino-3-nitrophenylboronic acid pinacol ester 18 (208.6 mg,
0.79 mmol) were dissolved in 3.3 mL of DMF in the presence of
2 mL of 2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon
bubbling, Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was in-
troduced and the reaction was performed at 80 ꢀC for 1 h (moni-
toring by TLC, cyclohexane/EtOAc 5:5). After workup 2-(40-amino-
3-nitrophenyl)-6-methylbenzothiazole 27 was isolated by filtra-
tion as a brown amorphous powder. Yield 182.7 mg (97%). Rf¼0.4,
SiO2 (cyclohexane/EtOAc 5:5). 1H NMR (DMSO-d6, 400 MHz)
d
¼8.61
0
0
0
0
0
0
(d,1H, H6 , J6 -2¼2.2 Hz), 8.06 (dd,1H, J2 -3¼8.9 Hz, J2 -6 ¼2.3 Hz, H2 ),
0
0
0
0
7.97 (sbroad, 1H, NH2); 7.90 (d, 1H, J7-5¼3.2 Hz, H7), 7.83 (d, 1H, J4-
d
¼9.35 (s, 1H, H7), 8.47 (m, 4H, H2 , H3 , H5 , H6 ), 8.43 (dd, 1H, J5-
0
0
¼8.2 Hz, H4), 7.35 (d, 1H, J5-4¼8.5 Hz, H5), 7.20 (d, 1H, J3 -2 ¼8.9 Hz,
¼9.0 Hz, J5-7¼2.3 Hz, H5), 8.37 (d, 2H, J4-5¼8.9 Hz, H4). 13C NMR
5
4
H3 ). 13C NMR (DMSO-d6, 100 MHz):
d
¼164.6 (C2), 151.5 (C9), 147.6
(DMSO-d6, 100 MHz):
d
¼166.6 (C2), 160.5 (C2), 145.7 (C6), 148.3
0
0
0
0
0
0
0
0
0
0
(C4 ), 134.8 (C8), 134.0 (C5 ), 133.4 (C2 ), 129.9 (C6), 128.0 (C5), 124.13
(C4 ), 139.6 (C1 ), 136.8 (C8), 133.3 (C2 and C6 ), 128.9 (C3 and C5 ),
128.3 (C4), 126.6 (C5), 124.0 (C7). HPLC purity: 99%, Krom Si 250,
0
0
0
(C6 ), 121.9 and 121.7 (C7 and C4), 120.2 (C1 ), 120.2 (C3 ), 21.1 (CH3).
HPLC purity: 92%, Krom Si 250, Heptane/AcOEt 30:70, 0.8 mL minꢂ1
,
Heptane/AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼338 nm, tR¼4.62 min. GC/
l
¼338 nm, tR¼5.58 min. GC/MS: method 180; tR¼10.36 min, m/z:
MS: method 180, tR¼9.95 min, m/z: 301 [M]þ (100), 271 [MꢂNO]þ
285 [M]þ (100), 239 [MꢂNO2]þ (60). IR (ATR):
n
3447 (
nNH2), 1628,
(30), 255 [MꢂNO2]þ (10), 209[Mꢂ2NO2]þ (60). IR (ATR):
n 1602,
1588
C
(
nC]C), 1252
(
nsNO2), 764
(d
CeH). HRMS: calcd for
1514 (nC]C), 1514,(nasNO2), 1330 (nsNO2), 853 (dCeH).
14H11N3O2SNH [MþH]þ (286.06447); found (286.06472).
4.3.16. 2-(40-Amino-3-nitrophenyl)-6-nitrobenzothiazole
(31). 2-
4.3.13. 2-(40-Aminophenyl)-6-nitrobenzothiazole (28). 2-Bromo-6-
nitrobenzothiazole 14 previously synthesized from 2-amino-6-
Bromo-6-nitrobenzothiazole 14 (170.9 mg, 0.66 mmol) and 4-
amino-3-nitrophenylboronic acid pinacol ester 18 (208.6 mg,
0.79 mmol) were dissolved in 3.3 mL of DMF in the presence of
2 mL of 2 M K2CO3 (4 mmol, 6.0 equiv). After 1 h under argon
bubbling, Pd(dppf)Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was in-
troduced and the reaction was performed at 80 ꢀC for 1 h (moni-
toring by TLC, cyclohexane/EtOAc 1:1). After workup 2-(40-amino-
3-nitrophenyl)-6-nitrobenzothiazole 31 was isolated by filtration
as a yellow amorphous powder. Yield 163.4 mg (78%). Rf¼0.3,
nitrobenzothiazole
(170.9
mg,
0.66
mmol)
and
4-
aminophenylboronic acid pinacol ester 11 (173.5 mg, 0.79 mmol)
were dissolved in 3.3 mL of DMF in the presence of 2 mL of 2 M K2CO3
(4 mmol, 6.0 equiv). After 1 h under argon bubbling, Pd(dppf)
Cl2$CH2Cl2 (26.9 mg, 0.033 mmol) was introduced and the reaction
was performed at 80 ꢀC for 2 h (monitoring by TLC, cyclohexane/
EtOAc 1:1). After workup 2-(40-aminophenyl)-6-nitrobenzothiazole
28 was isolated by filtration as a yellow amorphous powder. Yield
132.8 mg (74%). Rf¼0.4, SiO2 (cyclohexane/EtOAc 1:1). 1H NMR
SiO2 (cyclohexane/EtOAc 1:1). 1H NMR (DMSO-d6, 400 MHz)
d
¼9.10
0
0
0
(d, 1H, J7-5¼2.4 Hz, H7), 8.63 (d, 1H, J6 -2 ¼2.0 Hz, H6 ), 8.29 (dd, 1H,
0
(DMSO-d6, 400 MHz)
d
¼9.09 (s,1H, H7), 8.30 (d,1H, J5-4¼9.1 Hz, H5),
J5-4¼9 Hz, J5-7¼2.5 Hz, H5), 8.10 (d, 1H, J4-5¼8.7 Hz), 8.04 (dd, 1H, J2 -
0
0
0
0
0
0
0
0
0
0
0
0
8.02 (d, 2H, J4-5¼9.1 Hz, H4), 7.85 (d, 2H, J2 -3 or J6 -5 ¼8.3 Hz, H2 and
¼8.9 Hz, J2 -6 ¼2.9 Hz, H2 and H6 ), 7.18 (d, 1H, J3 -2 ¼9 Hz, H3). 13C
3
H6 ), 7.72 (d, 1H, J3 -2 or J5 -6 ¼8.4 Hz, H3), 6.22 (s, 1H, NH2); 13C NMR
NMR (DMSO-d6, 100 MHz):
d
¼171.9 (C2), 157.4 (C9), 148.3 (C6), 143.9
0
0
0
0
0
0
0
0
0
0
(DMSO-d6, 100 MHz):
d
¼174.5 (C2), 158.2 (C9), 153.3 (C4 ), 143.3 (C6),
(C4 ), 134.6 (C8), 133.6 (C2 ), 129.9 (C5 ), 125.3 (C6 ), 122.4 (C4), 121.8
0
0
0
0 0
(C5), 120.2 (C7), 119.2 (C1 ), 119.17 (C3 ). HPLC purity: 87%, Krom Si
134.3 (C8), 129.6 (C2 and C6 ), 121.8 (C4), 121.5 (C5), 119.2 (C1 ), 118.8
0
0
(C7), 113.6 (C3 and C5 ), HPLC purity: 64%, Krom Si 250, Heptane/
250, Heptane/AcOEt 50:50, 0.8 mL minꢂ1
,
l
¼362 nm, tR¼9.38 min.
AcOEt 50:50, 0.8 mL minꢂ1
,
l¼345 nm, tR¼8.7 min. GC/MS: method,
GC/MS: method 260; tR¼5.33 min, m/z: 316 [M]þ (100), 270
180, tR¼10.14 min, m/z: 271 [M]þ (100), 241 [MꢂNO]þ (25),
[MꢂNO2]þ (20), 224 [Mꢂ2NO2]þ(50). IR (ATR):
n 3472 (nNH2), 1638,
225 [MꢂNO2]þ(100). IR (ATR):
n
3396 (
n
NH2), 1636, 1570, 1502, 1436
1502 (
n
C]C), 1335 (nsNO2), HRMS: calcd for C13H8N4O4SH [MþH]þ
(n
C]C), 1328 (nsNO2), 832 (
dCeH). HRMS: calcd for C13H9N3O2SH
(317.03390); found (317.03387).
[MþH]þ (272.04882); found (272.04899).
4.3.17. 2-(40-Aminophenyl)-6-aminobenzothiazole (32). 2-Bromo-6-
aminobenzothiazole 15 (50 mg, 0.22 mmol) previously synthesized
from 2-bromo-6-nitrobenzothiazole 14 and 4-aminophenylboronic
acid pinacol ester 97% 11 (59.2 mg, 0.26 mmol) were dissolved in
4.3.14. 2-(60-Aminopyridin-3-yl)-6-nitrobenzothiazole
(29). 2-
Bromo-6-nitrobenzothiazole 14 (170.9 mg, 0.66 mmol) and 2-
aminopyridine-5-boronic acid pinacol ester 97% 16 (179.7 mg,

G. Bort et al. / Tetrahedron 69 (2013) 7345e7353
7353
18. Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D. P.;
1.5 mL of DMF in the presence of 0.7 mL of 2 M K2CO3 (1.32 mmol,
6.0 equiv). After 1 h under argon bubbling, Pd(dppf)Cl2$CH2Cl2 (9 mg,
0.011 mmol) was introduced and the reactionwas performed at 80 ꢀC
for 4 h (monitoring by TLC, cyclohexane/EtOAc 4:6). After workup 2-
(40-aminophenyl)-6-aminobenzothiazole 32 was isolated by filtra-
tion as a brown amorphous powder. Yield 43.5 mg (70%). Rf¼0.2,
€
Bergstrom, M.; Savitcheva, I.; Huang, G. F.; Estrada, S.; Ausen, B.; Debnath, M. L.;
Barletta, J.; Price, J. C.; Sandell, J.; Lopresti, B. J.; Wall, A.; Koivisto, P.; Antoni, G.;
ꢂ
€
Mathis, C. A.; Langstrom, B. Ann. Neurol. 2004, 55, 306.
19. Choi, S. R.; Golding, G.; Zhuang, Z.; Zhang, W.; Lim, N.; Hefti, F.; Benedum, T. E.;
Kilbourn, M. R.; Skovronsky, D.; Kung, H. F. J. Nucl. Med. 2009, 50, 1887.
20. Nelissen, N.; Van Laere, K.; Thurfjell, L.; Owenius, R.; Vandenbulcke, M.; Koole,
M.; Bormans, G.; Brooks, D. J.; Vandenberghe, R. J. Nucl. Med. 2009, 50, 1251.
21. Rowe, C. C.; Ackerman, U.; Browne, W.; Mulligan, R.; Pike, K. L.; O’Keefe, G.;
Tochon-Danguy, H.; Chan, G.; Berlangieri, S. U.; Jones, G.; Dickinson-Rowe, K. L.;
Kung, H. P.; Zhang, W.; Kung, M. P.; Skovronsky, D.; Dyrks, T.; Holl, G.; Krause, S.;
Friebe, M.; Lehman, L.; Lindemann, S.; Dinkelborg, L. M.; Masters, C. L.; Ville-
magne, V. L. Lancet Neurol. 2008, 7, 129.
SiO2 (cyclohexane/EtOAc 1:1). 1H NMR (DMSO-d6, 400 MHz)
d¼7.66
0
0
0
0
0
0
(d, 2H, J2 -3 or J6 -5 ¼8.4 Hz, H2 and H6 ), 7.59 (d, 1H, J4-5¼8.8 Hz, H4),
0
0
0
7.08 (s, 1H, H7), 6.76 (d, 1H, J5-4¼8.9 Hz, H5), 6.67 (d, 2H, J3 -2 or J5 -
¼8.5 Hz, H3 and H5 ), 5.64 (s, 1H, NH2). 13C NMR (DMSO-d6,
0
0
0
6
22. Nyberg, S.; Jonhagen, M. E.; Cselenyi, Z.; Halldin, C.; Julin, P.; Olsson, H.; Freund-
Levi, Y.; Andersson, J.; Varnas, K.; Svensson, S.; Farde, L. Eur. J. Nucl. Med. Mol.
Imaging 2009, 36, 1859.
0
0
100 MHz):
d
¼161.9 (C2), 155.1 (C4 ), 146.4 (C6 ), 145.4 (C9), 135.3 (C8),
0
0
0
0
0
127.9 (C2 and C6 ), 122.1 (C4), 120.9 (C1 ), 114.5 (C5), 113.6 (C3 and C5 )
104.1 (C7). HPLC purity: 95%, Krom Si 250, AcOEt 100%, 0.8 mL minꢂ1
,
23. Gravenfors, Y.; Jonasson, C.; Malmstroem, J.; Nordvall, G.; Pyring, D.; Slivo, C.;
Sohn, D.; Stroem, P.; Wensbo, D., 2007. WO 2007086800.
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T.; Price, J. C.; Mathis, C. A. J. Neurosci. 2005, 25, 10598.
l
¼345 nm, tR¼7.37 min. GC/MS: method 180, tR¼9.42 min, m/z: 241
[M]þ (100), IR (ATR):
n 3455 (nNH2),1604,1462 (nC]C),1288 (nCeN),
820 (
(242.07464).
d
C-H). HRMS: calcd for C13H11N3SH [MþH]þ (242.07464); found
26. Rowe, C. C.; Ng, S.; Ackermann, U.; Gong, S. J.; Pike, K.; Savage, G.; Cowie, T. F.;
Dickinson, K. L.; Maruff, P.; Darby, D.; Smith, C.; Woodward, M.; Merory, J.;
Tochon-Danguy, H.; O’Keefe, G.; Klunk, W. E.; Mathis, C. A.; Price, J. C.; Masters,
C. L.; Villemagne, V. L. Neurology 2007, 68, 1718.
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1509.
Acknowledgements
Financials supports from the Centre National de la Recherche
Scientifique (Cnrs) and Guerbet Group are gratefully acknowledged.
The authors also thank Annie Falguieres for technical assistance
during HPLC analyses.
ꢁ
Supplementary data
30. Mormino, E. C.; Brandel, M. G.; Madison, C. M.; Rabinovici, G. D.; Marks, S.;
Baker, S. L.; Jagust, W. J. Neuroimage 2012, 59, 1152.
31. Morris, J. C.; Roe, C. M.; Grant, E. A.; Head, D.; Goate, A. M.; Fagan, A. M.;
Holtzman, D. M.; Mintun, M. A. Arch. Neurol. 2009, 66, 1469.
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T. L. S.; Morris, J. C. Ann. Neurol. 2011, 70, 857.
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35. Wilson, A. A.; Garcia, A.; Chestakova, A.; Kung, H.; Houle, S. J. Labelled Compd.
Radiopharm. 2004, 47, 679.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.06.085.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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