A one-pot, two-step microwave-assisted synthesis of highly functionalized benzoxazoles using solid-supported reagents (SSRs)

Article abstract of DOI:10.1016/j.tetlet.2008.05.059

A one-pot, two-step protocol for the microwave-assisted solid-phase synthesis of substituted benzoxazoles has been developed starting from different polymer-bound esters we previously designed as solid-supported reagents (SSRs) for the acylation of amines, alcohols and phenols. The combination of a parallel synthesizer and a microwave reactor allowed to quickly prepare a collection of substituted benzoxaxoles in high purity and satisfactory yields. This protocol is amenable for automation and could be used for the preparation of combinatorial libraries in drug discovery programs.

Full text of DOI:10.1016/j.tetlet.2008.05.059

Tetrahedron Letters 49 (2008) 4464–4466
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A one-pot, two-step microwave-assisted synthesis of highly functionalized
benzoxazoles using solid-supported reagents (SSRs)
*
Marco Radi, Sara Saletti, Maurizio Botta
Dipartimento Farmaco Chimico Tecnologico, Universita’ di Siena, Via Aldo Moro, 53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot, two-step protocol for the microwave-assisted solid-phase synthesis of substituted benzoxaz-
oles has been developed starting from different polymer-bound esters we previously designed as solid-
supported reagents (SSRs) for the acylation of amines, alcohols and phenols. The combination of a parallel
synthesizer and a microwave reactor allowed to quickly prepare a collection of substituted benzoxaxoles
in high purity and satisfactory yields. This protocol is amenable for automation and could be used for the
preparation of combinatorial libraries in drug discovery programs.
Received 15 April 2008
Revised 9 May 2008
Accepted 13 May 2008
Available online 17 May 2008
Keywords:
Benzoxazoles
Ó 2008 Elsevier Ltd. All rights reserved.
Microwave
Solid-supported reagents
Combinatorial chemisrty
Substituted benzoxazoles have drawn significant attention due
to their biological activity and diverse medicinal uses such as
gram-positive antibacterial agents,1 antibiotics,2 antiparasitic,3
anti-inflammatory,4 elastase inhibitors,5 anti-stress ulcer,6 and
anticancer agents.7 There are two commonly used approaches for
the construction of the benzoxazole ring system: the first approach
involves the coupling of the 2-aminophenols with carboxylic acid
derivatives under strongly acidic conditions at high reaction tem-
peratures8 while the second approach uses the reaction of 2-ami-
nophenols with an aldehyde via the oxidative cyclization of
imine intermediates.9 Due to the high biological significance of
the benzoxazole scaffold, combinatorial chemistry techniques have
been applied to the synthesis of benzofused derivatives to be
screened in drug discovery programs. Although several reports
for the solid-phase synthesis (SPS) of benzothiazoles, and benzim-
idazoles have been published,10 a real need still exists for efficient
solid-phase procedures to be applied for the generation of highly
functionalized benzoxazole libraries. Hwang and Gong reported
the SPS of 2-aminobenzoxazole library using a safety-catch linker11
while Hioki et al. recently published the synthesis of benzothiaz-
oles, benzoxazoles and benzimidazoles using a traceless-linker.12
However, both these approaches suffer from long reaction times
and were applied to introduce a high level of functionalization at
the C2 position only.
series of solid-supported reagents (SSRs). We have previously re-
ported the development of pyrimidine-based SSRs and their appli-
cation to the microwave-assisted synthesis (MAS) of amides,
esters, and thioesters.13 Unexpectedly, when 2-amino-thiophenol
was submitted to the same protocol, the cyclodehydrated
O
O
N
i.
Cl
N
Cl
70%
S
2
S
N
Me
1
N
O
Cl
3
ii.
O
HO
Cl
HN
4
HN
O
Cl
Herein we report our results on the development of a one-pot,
two-step microwave-assisted protocol for the synthesis of benzox-
azoles functionalized at C2, C4, and C5 positions, starting from a
O
O
Cl
5
Scheme 1. Reagents and conditions: (i) 2-aminothiophenol, 160 °C, MW (open-
vessel mode), neat, 10 min; (ii) 2-aminophenol, 160 °C, MW (open-vessel mode),
neat, 10 min.
* Corresponding author. Tel.: +39 0577 234306; fax: +39 0577 234333.
E-mail address: botta@unisi.it (M. Botta).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.059

M. Radi et al. / Tetrahedron Letters 49 (2008) 4464–4466
4465
O
R1
O
O
R2
O
R1
R2
R2
O
HO
R3
R3
R3
ii.
N
i.
N
O
R1
O
Me
R1
N
S
N
R1
N
H
H
8
7
6
9
Scheme 2. Reagents and conditions: (i) substituted 2-aminophenols (see R2 and R3 in Table 1), MW, 300 W, sealed tube, neat, 10 min; (ii) polymer-bound p-toluenesulfonic
acid, toluene, MW, 180 °C, sealed tube, 10 min.
Table 1
benzothiazole was obtained as the only product. Optimization of
the previous protocol allowed to obtain the desired benzothiazole
Summary for the synthesis of benzoxazoles 9
2 in 70% yield and more than 95% purity after simple removal of
the resin by filtration (Scheme 1).
Entry
Loading of the SSRs 6
R1
R2
R3
Yield (%)
(mmol/g)a
Despite this, approach to the synthesis of benzothiazole deriva-
tives was noteworthy, similar results had already been obtained by
Janda using different polymer-bound esters in the presence of a Le-
wis acid.14 However, the Janda’s procedure suffered from two ma-
jor drawbacks: the need for a chromatographic purification in
order to obtain the pure products and its failure in the synthesis
of benzoxazole derivatives.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
0.353
0.750
0.404
0.287
0.275
0.265
0.338
4-Chlorp-Ph
4-Chlorp-Ph
4-Chlorp-Ph
4-Chlorp-Ph
2-Fluoro-Ph
2-Fluoro-Ph
2-Fluoro-Ph
2-Fluoro-Ph
2,4-Difluoro-Ph
2,4-Difluoro-Ph
2,4-Difluoro-Ph
2,4-Difluoro-Ph
2-Thiophenyl
2-Thiophenyl
2-Thiophenyl
2-Thiophenyl
4-Cyano-Ph
4-Cyano-Ph
4-Cyano-Ph
4-Cyano-Ph
3-Cyano-Ph
3-Cyano-Ph
3-Cyano-Ph
3-Cyano-Ph
Acetyl
H
NO2
H
H
H
NO2
H
H
H
NO2
H
H
H
NO2
H
H
H
NO2
H
H
H
H
H
Cl
Me
H
61
56
47
94
42
—
88
71
47
42
38
99
73
41
41
67
—
H
Cl
Me
H
Accordingly, we decided to focus our attention on the develop-
ment of a simple procedure for the synthesis of highly functional-
ized benzoxazoles. In a first attempt, we tried to apply the
optimized protocol described above to the synthesis of the benzox-
azole derivatives. The SSR 1 (1 equiv) was dissolved in 3 mL of
CH2Cl2 and swollen for 10 min; 2-aminophenol (1 equiv) was then
added and, after evaporation of the solvent, the reaction mixture
was irradiated at 160 °C for 10 min. Unfortunately the desired
benzoxazole 3 was never obtained while amide 4 together with a
small amount of the diacylated derivative 5 was isolated as the
only product after removal of the solid support by filtration
(Scheme 1). The liquid-phase synthesis of benzoxazoles starting
from analogues of compounds 4 and 5 in the presence of p-tolu-
enesulfonic acid has been previously reported by DeLuca and Ker-
win.15 Accordingly, we decided to develop a one-pot, two-step
procedure in which the product/s of the first step (4 and 5) could
be converted, in a second step, into the desired benzoxazole by
heating in the presence of p-toluenesulfonic acid (PTSA) polymer
bound which could be removed by filtration at the end of the reac-
tion. The optimized procedure is reported in Scheme 2:16 in the
first step, we reacted a series of SSRs (6)17 with an excess of differ-
ent aminophenols (2 equiv) to shift the equilibrium toward the for-
mation of the uncyclized intermediates (7 and 8). The PTSA-
polymer bound added in the second step allowed to scavenge the
unreacted basic species and to catalyze the cyclodehydration reac-
tion. Final removal of the combined solid supports by filtration al-
lowed to isolate the pure products 9 (Table 1).
Running the reactions into the 10 mL microwave vials, it was
possible to combine the characteristics of the Buchi Syncore paral-
lel synthesizer with that of the CEM microwave reactor in order to
speed up the generation of the combinatorial collection of benzox-
azoles 9: in the first step of the parallel synthesis,the reaction ves-
sels containing the adequate reaction mixture swelled in
dichloromethane, were placed into the syncore and evaporated in
parallel. The resulting neat reaction mixtures were then irradiated
into the microwave. In the second step, the Syncore was used for
the parallel filtration and washing of the resins. Parallel evapora-
tion of the filtrate afforded the pure benzoxazoles 9 (Scheme 2,
Table 1). As summarized in Table 1, our procedure allowed to
generate a collection of functionalized benzoxazoles (9) with an
high level of functional group tolerance: both electron-withdraw-
ing and electron-donating groups were well tolerated on the ami-
nophenol moiety while the only completely unreactive acylating
H
Cl
Me
H
H
Cl
Me
H
H
—
Cl
Me
H
50
24
—
NO2
H
H
H
NO2
H
H
—
Cl
Me
H
H
Cl
Me
57
31
—
—
—
Acetyl
Acetyl
Acetyl
H
—
a
The loading was calculated as described in Ref. 17.
species was proved to be the acetyl-SSR. In the case of entries 6,
17–18, 21–22, and 25–28 the benzoxazoles were not formed since
the uncyclized intermediates were never obtained.
In conclusion, an efficient one-pot, two-step protocol for the
microwave-assisted solid-phase synthesis of substituted benzox-
azoles has been developed starting from acylating solid-supported
reagents (6). The combination of a parallel synthesizer and a
microwave reactor allowed to quickly prepare a collection of
highly functionalized benzoxaxoles 9. This protocol is amenable
for automation and could be used for the preparation of combina-
torial libraries in drug discovery programs.
Acknowledgments
The University of Siena is greatly acknowledged for financial
support. We also acknowledge Dr. Elena Petricci for helpful
discussion.
References and notes
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microwave power delivery system with operator-selectable power output
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floor of the microwave cavity and a Teflon-coated magnetic stir bar in the
vessel. General procedure for the synthesis of benzoxazoles 9: the SSRs 6 (1 equiv)
were partitioned into four different microwave tubes, each placed within the
Syncore and swelled in CH2Cl2 (3 mL) for 10 min. The required aminophenols
were added, the resulting mixture stirred for additional 10 min, and finally
evaporated in parallel (14 per time). The neat crude mixtures were irradiated
into the microwave at 300 W for 10 min each. The resins were then swelled
with toluene (3 mL), PTSA-polymer bound (8 equiv) was added and the
resulting mixtures were irradiated into the microwave for 10 min at 180 °C.
The combined solid supports were removed by parallel filtration then
evaporation and trituration with hexane gave the desired benzoxazoles 9 in
high purity.
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their loading was calculated by cleavage of the corresponding benzylamides:
considering the theoretical loading of the SSR equal to that of the Merrifield
resin (1.25 mmol/g), reaction with 1.25 mmol of benzylamine gave an amount
of benzylamide equal to the real loading (see Table 1).
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