A simple and efficient one step synthesis of benzoxazoles and benzimidazoles from carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2006.05.052

Benzoxazoles or benzimidazoles can be rapidly and efficiently synthesized from a variety of carboxylic acids with 2-aminophenols or 1,2-phenylenediamines in one simple step, respectively. The use of commercially available PS-PPh₃ resin combined with microwave heating delivered a variety of benzoxazoles and benzimidazoles in high yields and purities.

Full text of DOI:10.1016/j.tetlet.2006.05.052

Tetrahedron Letters 47 (2006) 4823–4826
A simple and efficient one step synthesis of benzoxazoles and
benzimidazoles from carboxylic acids
Ying Wang,* Kathy Sarris, Daryl R. Sauer and Stevan W. Djuric
High-Throughput Organic Synthesis Group, Medicinal Chemistry Technologies, Global Pharmaceutical Research and
Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6113, United States
Received 20 April 2006; revised 5 May 2006; accepted 9 May 2006
Abstract—Benzoxazoles or benzimidazoles can be rapidly and efficiently synthesized from a variety of carboxylic acids with 2-amino-
phenols or 1,2-phenylenediamines in one simple step, respectively. The use of commercially available PS-PPh3 resin combined with
microwave heating delivered a variety of benzoxazoles and benzimidazoles in high yields and purities.
Ó 2006 Elsevier Ltd. All rights reserved.
Lead optimization is one of the most critical phases
within the drug discovery paradigm. Lead compounds
must display favorable properties for further develop-
ment, including desirable chemical features that can
facilitate medicinal chemistry optimization efforts.1 Fre-
quently, a critical part of the lead molecular skeleton has
been studied and shown to be crucial for a particular
biological activity, while other parts of the molecular
skeleton need chemical modifications so as to achieve
the desired properties of a development candidate. Such
processes include fine tuning the activity through SAR
studies and improving the selectivity and pharmaco-
kinetics of the lead compound.
To this end, we have been actively involved in the prep-
aration of diverse biologically relevant heterocycles
from precursors containing common chemical function-
alities. In recent letters, we have reported general and
efficient reaction protocols for the preparation of
1,2,4-oxadiazoles 12 and 1,3,4-oxadiazoles 2.3 Notably,
both methods start from easily accessible carboxylic
acids as the common precursor and utilize the same re-
agent combination PS-PPh3/CCl3CN4 under microwave
heating conditions. The key advantage of this approach
is that from a common carboxylic acid scaffold, by sim-
ply using common reagents and a common operation,
distinct structures can be easily accessed by utilizing a
matrix of distinct monomer units (Fig. 1). In this letter,
we report the further extension of our strategy to synthe-
size benzoxazoles 3 and benzimidazoles 4, both of which
Over the past decade, focused libraries have been suc-
cessfully utilized throughout the lead optimization pro-
cess in order to incorporate modifications to targeted
regions of the lead molecular skeleton, which in turn,
helps to establish initial SAR studies and determine
future optimization strategies. Frequently, analogs bear-
ing this common molecular skeleton differ only by dis-
crete and different substituents. It is in this context
then, that in order to increase the chance of finding an
optimal drug candidate, our goal has been to maximize
the structural complexity and skeletal diversity of a
library whilst still maintaining critical pharmacophores,
hence differing from the traditional focused library
approach.
O
R'
R
N
H
O
N
O
N
R'
R'
R
R
N
R'
R'
1
3
4
O
R''(H)
N
O
R
R
OH
N
N
R
R= Aryl, Alkyl
N
2
*
Figure 1. Syntheses of diverse structural motifs from carboxylic acid
Corresponding author. Tel.: +1 847 935 3058; fax: +1 847 935
with PS-PPh3/CCl3CN.
5212; e-mail: wang.ying@abbott.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.052

4824
Y. Wang et al. / Tetrahedron Letters 47 (2006) 4823–4826
are important structural motifs in drug discovery pro-
grams, from carboxylic acids (Fig. 1).5
fact that the reaction was very easy to workup by simple
filtration of the resin and evaporation of the solvents. In
many cases, simple flash chromatography afforded the
desired benzoxazole in high purity.7
Common synthetic routes to benzoxazoles and benzim-
idazoles have typically involved coupling of carboxylic
acids or their derivatives with 2-aminophenols or 1,2-
phenylenediamines in the presence of strong acids at
high temperatures.6 As mentioned previously, we have
shown that the reagent combination of PS-PPh3 and
CCl3CN is particularly effective in enabling the transfor-
mation of carboxylic acids into their corresponding
1,2,4-oxadiazole and 1,3,4-oxadiazole derivatives in a
facile manner. We were delighted to find that the same
reagent combination also worked equally well for the
expeditious generation of benzoxazoles and benzimidaz-
oles from carboxylic acids.
Naturally, having now developed a general and efficient
protocol for benzoxazole synthesis starting from 2-
aminophenol and carboxylic acid, we wondered if sub-
stitution of the 2-aminophenol scaffold with 2-aminothio-
phenol and 1,2-phenylenediamines, would allow access
Table 2. Synthesis of benzoxazoles from carboxylic acids and 1,2-
aminophenol with PS-PPh3/CCl3CN
2 equiv. CCl3CN
3 equiv. PS-PPh3
OH
O
N
O
+
R2
R2
R1
(1 equiv.)
CH3CN, MW
150 ºC, 15 mins
R
OH
1
NH2
Benzoic acid 5 and 2-aminophenol 6 were chosen for the
model study. When the reaction was carried out in
CH2Cl2 or CH3CN at room temperature for an ex-
tended 20 h period, only the acylation product 7 was ob-
served by LC/MS analysis along with other unidentified
peaks. At higher temperature (75 °C) in CH3CN, we
were able to obtain the desired product although the
reaction was not clean as observed from crude LC/MS
analysis. Optimal result was obtained when the reaction
mixture was heated in the microwave at 150 °C for
15 min in acetonitrile. Inferior results were obtained
when either the reaction temperature was lowered to
140 °C or the reaction time was cut to 10 min. With
1.5 equiv of CCl3CN, both the acylated product 7 and
the cyclized product 8 were observed by LC/MS analysis
of the crude mixture. Exploitation of microwave tech-
nology allowed us to quickly identify the optimized reac-
tion conditions within a short time frame (Table 1).
Entry
1
Product
Yielda (%)
97
N
O
N
O
2
3
93
79
NO2
N
O
N
4
85
94
83
89
77
85
93
94
86
O
Cl
N
5
O
N
O
O
6
O
With this protocol at hand, we quickly found that this
one step procedure worked well for a variety of alkyl
and aryl carboxylic acids as well as a diverse selection
of 2-aminophenols (Table 2). Of particular note is the
N
7
O
N
O
8
Table 1. Optimization of reaction conditions for the synthesis of
representative benzoxazole 8
N
O
9
O
OH
Cl
OH
N
10
11
12
5
+
3 equiv. PS-PPh3
2 equiv. CCl3CN
O
O
O
HN
N
NH2
OH
N
O
S
N
7
8
6
N
O
Entry
Reaction condition
7 (%)a
8 (%)a
CN
c
1
2
3
4
5
6
CH2Cl2, rt, >20 h
CH3CN, rt, >20 h
CH3CN, 75 °C, >14 h
MW, CH3CN, 140 °C, 15 min
MW, CH3CN, 150 °C, 10 min
MW, CH3CN, 150 °C, 15 min
90
55
15
—
—
—
—
80
70
80
97
c
N
13
14
80
91
b
O
b
b
—
N
O
N
a Conversion based on crude LC/MS analysis.
b The % conversion was not determined.
c Trace amount of 8 was observed.
a Isolated yield after purification.

Y. Wang et al. / Tetrahedron Letters 47 (2006) 4823–4826
4825
to the corresponding benzthiazole and benzimidazole
derivatives. In practice, with 2-aminothiophenol under
the same reaction conditions, the desired benzthiazole
was obtained along with several side products as shown
from the crude LC/MS analysis and the isolated yield
was low. No further attempts were made to optimize
the protocol with this reagent system and attention
was focused on the benzimidazoles. Gratifyingly, with
1,2-phenylenediamines, again under the same reaction
conditions, benzimidazoles were obtained with high
yields and purities. As with the benzoxazoles, this proto-
col worked for a variety of carboxylic acids and 1,2-
phenylenediamines to afford the corresponding benz-
imidazole in good yields in a single step (Table 3).7 Sig-
nificantly, fair to good yields of the corresponding
benzimidazoles were also obtained with electron defi-
cient 4,5-dichlorobenzene-1,2-diamine (Table 3, entries
2 and 10), which is generally a recalcitrant substrate
for acylation paradigms.
Table 3. Synthesis of benzoxazoles from carboxylic acids and 1,2-
phenylenediamine with PS-PPh3/CCl3CN
2 equiv. CCl3CN
N
N
3 equiv. PS-PPh3
NH2
O
R2
+
R1
R2
(1 equiv.)
CH3CN, MW
R
OH
1
NH
150 ºC, 15 mins
R3(H)
R3(H)
In summary, we have developed an efficient and general
reaction protocol for the synthesis of benzoxazoles and
benzimidazoles starting from carboxylic acids. The gen-
erality of these reactions, as demonstrated in Tables 2
and 3, is important for library analog production as di-
verse substituent patterns are often used with one set of
reaction conditions in a single library. More impor-
tantly, the methods we have developed fit into our over-
all strategy where starting from a common precursor, in
our case a carboxylic acid, using a combination of the
same reagents and a common operation, multiple het-
erocyclic scaffolds with distinct structure complexity
and diversity can be easily accessed. We believe that this
approach combines the advantages of both focused
library synthesis and diversity-oriented synthesis. Because
of the generality of the reaction protocols that we have
been developed, thorough SAR studies are possible
within the structure skeletons that are constructed.
More importantly, diverse structure skeletons can also
be obtained within one library to greatly facilitate either
a hit to lead or the lead optimization process.
Entry
1
Product
Yielda (%)
N
79
N
H
Cl
Cl
N
2
76
N
H
N
3
4
5
6
94
87
89
85
N
H
N
N
H
N
N
H
N
N
H
N
N
7
8
93
80
O
O
Supplementary data
N
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
05.052.
N
H
N
9
90
90
N
H
Cl
Cl
N
References and notes
10
N
H
1. For some reviews, see: (a) Bleicher, K. H.; Bo¨hm, H.;
N
Muller, K.; Alanine, A. Nature Rev. 2003, 2, 369–378; (b)
¨
11
12
83
89
Hann, M. M.; Leach, A. R.; Harper, G. J. Chem. Inf.
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2001, 41, 1308–1315.
N
H
N
N
H
2. Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W. Org.
Lett. 2005, 7, 925–928.
3. Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett.
2006, 47, 105–108.
4. For the use of CCl3CN/PS-PPh3 in acylation, see: (a) Jang,
D. O.; Park, D. J.; Kim, J. Tetrahedron Lett. 1999, 43,
5323–5326; (b) Buchstaller, H.; Ebert, H. M.; Anlauf, U.
Synth. Commun. 2001, 31, 1001–1005.
H
N
13
14
80
69
N
N
H
N
N
5. For some examples, see: (a) Griengl, A. H.; Petsch, M.;
Schoo, P. N.; Weber, H. Tetrahedron: Asymmetry 1996, 7,
473–490; (b) Clemens, J. J.; Davis, M. D.; Lynch, K. R.;
Macdonold, T. L. Bioorg. Med. Chem. Lett. 2004, 14, 4903–
a Isolated yields after purification.

4826
Y. Wang et al. / Tetrahedron Letters 47 (2006) 4823–4826
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7. General procedure: A Smith process vial (0.5–2 mL) was
charged with a stir bar. To the vessel were added 0.2 mmol
of the carboxylic acid and 0.2 mmol of the 2-aminophenol
or 1,2-phenylenediamine in 1.5 mL dry CH3CN. 0.6 mmol
PS-PPh3 (3 mmol/g) was added to the reaction mixture
followed by 0.4 mmol CCl3CN. The reaction vessel was
sealed and heated in microwave to 150 °C for 15 min. After
cooling, the reaction vessel was uncapped and the resin was
filtered and washed by additional CH3CN and MeOH. The
desired benzoxazole or benzimidazole was isolated by flash
chromatography. All products thus obtained were greater
than 98% pure as determined by LC/MS and 1H NMR
analysis.
6. For some recent examples using other methods, see: (a)
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