Solid-phase synthesis of benzothiazoles using an alkoxyamine linker

Article abstract of DOI:10.1016/j.tetlet.2012.06.008

An alkoxyamine linker was applied for the solid-phase synthesis of benzothiazoles. The substrate was anchored by aldoxime linkage and products were cleaved from the solid-support by aldoxime-imine exchange coupled with air-oxidation under the weakly acidi

Full text of DOI:10.1016/j.tetlet.2012.06.008

Tetrahedron Letters 53 (2012) 4337–4342
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Tetrahedron Letters
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Solid-phase synthesis of benzothiazoles using an alkoxyamine linker
Hideaki Hioki a, , Kimihito Matsushita b, Takeshi Noda c, Kota Yamaguchi a, Miwa Kubo b, Kenichi Harada b,
⇑
Yoshiyasu Fukuyama b
a Faculty of Education, Gunma University, Maebashi, Gunma 371-8510, Japan
b Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
c Department of Applied Bioscience, Kanagawa Institute of Technology, Atsugi, Kanagawa 243-0292, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An alkoxyamine linker was applied for the solid-phase synthesis of benzothiazoles. The substrate was
anchored by aldoxime linkage and products were cleaved from the solid-support by aldoxime–imine
exchange coupled with air-oxidation under the weakly acidic conditions. The tether is highly robust
under Mitsunobu reaction, nucleophilic substitution reaction, and Pd-catalyzed reaction conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 12 May 2012
Revised 31 May 2012
Accepted 4 June 2012
Available online 12 June 2012
Keywords:
Solid-phase synthesis
Benzothiazole
Alkoxyamine linker
Mitsunobu reaction
Pd-catalyzed reaction
Solid-phase organic synthesis (SPOS) provides a useful tool for
the preparation of a large number of compounds because products
are synthesized in easy operations. SPOS has been applied for the
synthesis of many nitrogen heterocycles, which are utilized in var-
ious fields such as medicinal and material chemistry.1–3 Linkers,
which connect substrates to solid-support, play an important role
in SPOS. Linkers, which should be easy to load starting materials
onto the solid support, must be stable under the various reaction
conditions to construct the desired products as well as must be
cleavable without damage to the product at the final stage. Many
types of linkers have been developed to efficiently build the de-
sired compounds.4–6 Previously, we developed a new aniline linker
1 for the solid-phase synthesis of heterocyclic compounds such as
2-substituted benz-fused azoles 7, quinazolines 8, and quinazoli-
nones 9 (Scheme 1).7–9 Linker 1 is characterized as a traceless lin-
ker, in which no functional group of the target molecules is
necessary to attach to a solid support.10–12 Substrates are anchored
by azomethine linkage and products are released from the solid-
support by imine-exchange reaction coupled with air-oxidation
in the reaction process. Although this azomethine linkage is stable
under some reaction conditions, it is susceptible to cleavage by
some nucleophiles.8 Thus SPOS employing the linker 1 can be ap-
plied only to limited reactions.
Recently we reported a new traceless alkoxyamine linker 10,
which can anchor ketones as ketoximes on a solid-support. It
was applied to the solid-phase synthesis of benzodiazepins 13
(Scheme 2).13 In the present study, we investigated the employ-
ment of the linker 10 for the preparation of benz-fused azoles by
loading benzaldehydes as aldoximes and by releasing the products
through aldoxime–imine exchange coupled with air-oxidation. If
loading the substrates and releasing the products are performed
in the same manner as the alkoxyaniline linker 1, this methodology
would be extended to the preparation of various benz-fuzed azoles
because aldoxime linkage is much more robust than azomethine
linkage under various conditions.
We first explored the reaction of aldoxime 15 with various
2-substituted anilines 6 in air to afford benzoannelated nitrogen
heterocycles 17, 18, and 19 by successive aldoxime–imine ex-
change reaction and air-oxidation. The results are summarized in
Table 1. In contrast to the reaction of azomethines with 2-amino-
thiophenol (6, Y = S, Scheme 1), the reaction of 15 with 6 (Y = S) un-
der an atmosphere did not proceed smoothly even at elevated
temperature (entries 1 and 2). The yield was drastically improved
by addition of trifluoroacetic acid to accelerate aldoxime–imine ex-
change (entry 3). The reaction was completed within 18 h (entry
4). However, treatment of 15 with 1,2-phenylenediamine
6
(Y = NH) did not give the desired benzimidazole 17 (Y = NH) under
the same reaction conditions (entry 6). Synthesis of benzoxazole
17 (Y = O), quinazoline 18, and quinazolinone 19 were also unsuc-
cessful even in the presence of DarcoÒ KB (entries 7–12), which
⇑
Corresponding author. Tel./fax: +81 27 220 7285.
E-mail address: hioki@gunma-u.ac.jp (H. Hioki).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.008

4338
H. Hioki et al. / Tetrahedron Letters 53 (2012) 4337–4342
O
R2
O
OH
R2
O
OH
N
NH2
2
H
O
O
N
O
4
N
O
4
H
H
3
1
NH2
YH
O
R2
6
XR1
R1XH
Y = S, NH, O,
N
O
X = S, NH, O
CH2NH, CONH
4
N
H
O
4
[O]
5
O
O
O
R2
R2
R2
XR1
XR1
XR1
N
N
O
N
Y
N
NH
Y = CH2NH
Y = S, NH, O
Y = CONH
7
8
9
Scheme 1. Combinatorial synthesis of benz-fuzed heterocycles using alkoxyaniline linker 1.
O
NH2
R
Me
N
O
OH
BocHN
O
R
11
O
12
N
MeI
N
H
ONH2
H+
4
10
13
Scheme 2. Solid-phase synthesis of benzodiazepins 13 using alkoxyamine linker 10.
was an effective catalyst for the oxidative cleavage from resin-
bound azomethine.8 Small amount of the products 17 (Y = O) and
19 were obtained at elevated temperature (entries 8 and 12). In en-
tries 6, 8, 10, and 12, 2-substituted anilines 6 were not detected
after the reaction. These results indicated that the aldoxime–imine
exchange of 15 with 6 was much slower than the imine–imine ex-
change of 5 with 6 and that oxidative decomposition of 6 pro-
ceeded more rapidly than aldoxime–imine exchange at higher
temperature. Only the benzothiazole 17 (Y = S) was obtained in
good yield because the air oxidation proceeds at rt.
Two kinds of palladium catalyzed reactions of 4-bromobenzal-
dehyde aldoxime 28 were also explored. Suzuki–Miyaura coupling
of aryl bromide 28 with phenylboronic acid (29) proceeded
smoothly to give the desired product 30 (Table 2). The reaction
was faster by treatment of Pd(OAc)2–PPh3 (1:3) system than by
that of Pd(PPh3)4 (entries 1 and 2). Employment of PdCl2(dppf)
gave 30 in the best yield (97%) (entry 3). Mizoroki–Heck reaction
of 28 with n-butyl acrylate (31) was performed by treating
PdCl2(dppf) and triethylamine at 100 °C. The desired product 32
was obtained in acceptable yield (entry 4).
From the preliminary experimental results described above, we
focused on the synthesis of benzothiazoles on a solid-support by
using alkoxyamine linker 10 shown in Scheme 3. p-Anisaldehyde
(14) was anchored by simple treatment with 10 in DMF at rt.
The resulting resin-bound aldoxime 20 was mixed with 4 equiv
of 2-aminothiophenol (21) in 5% TFA 1,2-dichloroethane solution
at rt for 18 h. The desired benzothiazole 22 was obtained in 82%
yield.
In advance of investigation of some reactions on a solid-sup-
port, the reaction conditions were optimized in solution. Two ap-
proaches were tried for alkylation of phenolic hydroxy group on
23. Mitsunobu reaction with 2-butanol smoothly proceeds to give
2-butyl ether 25 at rt in good yield (Scheme 4). n-Pentyl ether was
also obtained in good yield by alkylation with n-pentyl iodide un-
der the basic conditions. The reaction was slower than Mitsunobu
reaction.
Finally, these optimized conditions were applied to the solid-
phase synthesis by using alkoxyamine linker 10. The yields were
compared with that of the reaction using alkoxyaniline linker 1,
which was previously employed for the synthesis of heterocyclic
compounds.8 In case of Mitsunobu reaction on a solid-support,
the desired benzothiazole 36 was obtained in 80% yield by succes-
sive loading of 4-hydroxybenzaldehyde (33), Mitsunobu reaction
with 2-butanol (24), and aldoxime–imine exchange by using 2-
aminothiophenol (21) coupled with air-oxidation. Mitsunobu reac-
tion in the second step was completed within 4 h (Table 3, entries 1
and 2). On the other hand, the yields were moderate in the case of
using alkoxyaniline linker 1 (entries 3 and 4). Partial alcoholysis of
azomethine linkage with 2-butanol may occur during Mitsunobu
reaction.
The results for the alkylation of phenolic oxygen on a solid-
support with n-pentyl iodide under the basic conditions are

H. Hioki et al. / Tetrahedron Letters 53 (2012) 4337–4342
4339
Table 1
Scope and limitation of using aldoxime–imine exchange reaction for the synthesis of benz-fuzed heterocyles
OMe
NH2
N
YH
Y
6
Y = S, NH, O,
17 Y = S, NH, O
CH2NH,
OMe
CONH
OMe
OMe
N
MeONH3Cl
N
O
air, conditions
MeO
N
DMF, rt,
30 min
H
15
14
18
OMe
94%
(E:Z = 10:1)
N
O
NH
19
Entry
Y
S
Additive
Solvent
Temp
Period (H)
Yield (%)
1
2
3
4
DMF
DCE
DCE
DCE
100 °C
Reflux
rt
5
5
5
18
0
5
71
88
TFA(5%)
TFA(5%)
rt
5
6
NH
O
TFA(5%)
TFA(5%)
DCE
DCE
rt
Reflux
18
18
0
0
7
8
TFA(5%)
DCE
DCE
rt
Reflux
18
18
0
6
TFA(5%), DarcoÒ KB
9
CH2NH
CONH
TFA(5%)
DCE
DCE
DCE
DCE
rt
Reflux
rt
18
18
18
70
0
0
0
2
10
11
12
TFA(5%), DarcoÒ KB
TFA(5%)
TFA(5%)
Reflux
OMe
(entry 1). In our previous study of solid-phase synthesis of ben-
zodiazepins, the reactivity of N-alkylation of N-aryl amides highly
depended on solid-support. The polystylene resin cross-linked with
1% divinylbenzene was found to be the most suitable resin for the
N-alkylation by alkyl halides under the basic conditions.13 Thus
the solid-support was switched to the polystylene resin. The yield
was improved to 74% (entry 2). Similar results were obtained when
the aldehyde 33 was linked with 1 through azomethine linkage
(entries 3 and 4). However the overall yields by using alkoxyaniline
linker 1 were lower than that by alkoxyamine linker 10.
Suzuki–Miyaura coupling on a solid-support also proceeded
smoothly using the linker 10. The results are shown in Table 5.14
Employment of PdCl2(dppf) as a catalyst rather than Pd(OAc)2–
PPh3 gave better result as well as in solution phase reaction shown
in Table 2 (entries 2 and 3). The yields were dropped when 4-bromo-
benzaldehyde (38) was anchored as azomethine using 1 (entries 3
and 4). The substrate might be released during the Suzuki–Miyaura
O
OMe
O
O
14
H
N
N
H
N
H
O
ONH2
4
4
DMF, rt, 24 h
20
10
NH2
SH
OMe
N
S
21
5% TFA, DCE, rt, 18 h
82% in steps
22
Scheme 3. Synthesis of benzothiazole on a solid-support by using 10.
summarized in Table 4. The benzothiazole 37 was obtained in mod-
erate yield when the aldehyde 33 was anchored as aldoxime linkage
HO
O
OH
24
N
N
MeO
MeO
25
DIAD, PPh3, DCM, rt, 1 h
23
91%
(E:Z = 10:1)
I
O
26
K2CO3, DMF, rt, 3 h
N
23
MeO
94%
27
Scheme 4. Alkylation of phenolic hydroxy group on 23.

4340
H. Hioki et al. / Tetrahedron Letters 53 (2012) 4337–4342
Table 2
Suzuki–Miyaura coupling and Mizoroki–Heck reaction of 28
(HO)2B
Br
29
N
N
MeO
MeO
Na2CO3, DME, H2O, reflux
Conditions
30
32
28
28
O
O
OnBu
OnBu
31
N
MeO
Et3N, DMF, 100 °C
Conditions
Entry
Reagent
Catalyst (mol %)
Ligand (mol %)
Period
Yield (%)
1
2
3
29
29
29
Pd(PPh3)4 (10)
Pd(OAc)2(10)
PdCl2(dppf) (10)
—
2 h
45 min
45 min
92
84
97
PPh3 (30)
—
4
31
PdCl2(dppf) (20)
—
3 h
78
Table 3
Mitsunobu reaction on a solid-support by using 1 and 10
OH
HO
O
OH
O
H
33
N
24
N
X
1
10
or
4
DIAD, PPh3
DCM, rt, time
DMF, rt, 24 h
H
34
X = O, OAr
NH2
SH
O
O
N
21
O
N
S
X = O
5% TFA in DCE
rt, 18 h (linker 10)
N
H
X
4
36
35
X = O, OAr
X = OAr
DMF, 100 °C, 1 h
(linker 1)
Entry
Linker
10
Perioda (h)
Yieldb (%)
1
2
4
16
80
80
3
4
1
4
16
53
61
a
Reaction period for Mitsunobu reaction.
Isolated yield from 1 or 10.
b
coupling because unreacted intermediates or decomposed products
derived from 38 were not detected in the crude product 39.
A similar trend was observed in the Mizoroki–Heck reaction on
a solid-support (Scheme 5). The desired product 40 was obtained
in 68% overall yield by treatment of linker 10, whereas the yield
was decreased to 28% in the case of linker 1.
In conclusion, we found the alkoxyamine linker 10 is efficient
for the solid-phase synthesis of various benzothiazoles. The
aromatic aldehydes are tethered as aldoxime linkage and oxidatively
cleaved with 2-aminothiophenol under mildly acidic conditions in
air. The substrates on a solid-support can be subjected to Mitsun-
obu reaction, alkylation with alkyl halides, and palladium cata-
lyzed reactions such as Suzuki–Miyaura coupling and Mizoroki–
Heck reaction. The tether is highly robust under these reaction con-
ditions in comparison of azomethine linkage formed by aromatic
aldehydes and alkoxyaniline linker 1. Recyclability of the alkoxy-
amine linker 10 and application to the synthesis of benzothiazole
library is currently under investigation.

H. Hioki et al. / Tetrahedron Letters 53 (2012) 4337–4342
4341
Table 4
Alkylation of phenolic oxygen on a solid-support under the basic conditions by using 1 and 10
OH
O
NH2
SH
O
H
33
I
N
1 or 10
21
DMF, rt, 24 h
K2CO3, DMF,
rt, 55 h
S
5% TFA in DCM
rt, 18 h (linker 10)
37
or DMF, 100 °C,
1 h (linker 1)
Entry
Linker
10
Resin
Yielda (%)
1
2
LanternÒ
Polystylene
52
74
3
4
1
LanternÒ
Polystylene
14
63
a
Isolated yield from 1 or 10.
Table 5
Suzuki–Miyaura coupling on a solid-support by using 1 and 10
Br
O
NH2
SH
Ph
(HO)2B
H
38
29
N
1 or 10
21
(Lantern®)
DMF, rt, 24 h
Na2CO3,
catalyst (10 mol%),
DME, H2O
S
5% TFA in DCM
rt, 18 h (linker 10)
39
16 h, reflux
or DMF, 100 °C,
1 h (linker 1)
Entry
Linker
10
Catalysta
Ligand (mol%)a
Yieldb (%)
1
2
Pd(OAc)2
PdCl2(dppf)
PPh3 (10)
—
71
89
3
4
1
Pd(OAc)2
PdCl2(dppf)
PPh3 (10)
—
38
39
a
Catalysts and ligands for Suzuki–Miyaura coupling.
Isolated yield from 1 or 10.
b
Br
O
O
O
NH2
SH
OnBu
H
OnBu
38
31
N
S
1 or 10
21
DMF, rt, 24 h
(Lantern®)
PdCl2(dppf),
Et3N
DMF, 10 h,
100 °C
5% TFA in DCM
rt, 18 h (linker 10)
40
68% from 10
28% from 1
or DMF, 100 °C,
1 h (linker 1)
Scheme 5. Mizoroki–Heck reaction on a solid-support by using 1 and 10.
Acknowledgments
Reference and notes
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This study was financially supported by a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science, and Technology of
the Japanese Government (No.18590024) and Sasakawa Scientific
Research Grant from the Japan Science Society.

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reacted with 4-bromobenzaldehyde (55 mg, 0.3 mmol, 4 equiv) in DMF
solution (3 mL) at rt for 24 h. The solution was removed by decantation and
the resulting resins were washed with DMF (3 Â 2 min) and DCM (3 Â 2 min).
The resulting solid supported aldoxime was mixed with phenylboronic acid
(55 mg, 0.45 mmol, 6 equiv) and PdCl2(dppf)ÁCH2Cl2 in degassed
dimethoxyethane (4.2 mL) and 2 mol LÀ1 aqueous Na2CO3 solution (300
lL,
0.6 mmol, 8 equiv). The mixture was refluxed for 16 h. The solution was
removed by decantation and the resulting resin was washed with MeOH
(3 Â 2 min), DMF (3 Â 2 min), and DCM (3 Â 2 min). The resin was reacted with
2-aminothiophenol (32.7 lL, 0.3 mmol, 4 equiv) in 5% TFA-DCM solution
(3 mL) at rt under an air atmosphere for 18 h. The resulting resins were
washed with DMF (3 Â 2 min) and DCM (3 Â 2 min). The combined DMF and
DCM solutions were evaporated and purified by silica gel chromatography
(hexane/EtOAc = 20/1) to give benzothiazole 39 in 89% yield (19.1 mg,
14. Representative procedure for the synthesis of benzothiazoles:
66.5 lmol,) as a colorless solid (mp 130 °C, dec.).
One piece of the solid supported alkoxyamine 10 (loading: 75 l
mol)13 was